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A state-of-the-art review on LSD1 and its inhibitors in breast cancer: Molecular mechanisms and therapeutic significance

Frontiers in Pharmacology

September 2022
13:989575

DOI:10.3389/fphar.2022.989575

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CC BY 4.0

Authors:

Yang Guanjun

Ningbo University

Yan-Jun Liu

Fudan University

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Breast cancer (BC) is a kind of malignant cancer in women, and it has become the most diagnosed cancer worldwide since 2020. Histone methylation is a common biological epigenetic modification mediating varieties of physiological and pathological processes. Lysine-specific demethylase 1 (LSD1), a first identified histone demethylase, mediates the removal of methyl groups from histones H3K4me1/2 and H3K9me1/2 and plays a crucial role in varieties of cancer progression. It is also specifically amplified in breast cancer and contributes to BC tumorigenesis and drug resistance via both demethylase and non-demethylase manners. This review will provide insight into the overview structure of LSD1, summarize its action mechanisms in BC, describe the therapeutic potential of LSD1 inhibitors in BC, and prospect the current opportunities and challenges of targeting LSD1 for BC therapy.

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A state-of-the-art review on

LSD1 and its inhibitors in breast

cancer: Molecular mechanisms

and therapeutic signiﬁcance

Guan-Jun Yang

, Yan-Jun Liu

, Li-Jian Ding

, Fan Tao

Ming-Hui Zhu

, Zhen-Yuan Shi

, Juan-Ming Wen

Meng-Yao Niu

, Xiang Li

, Zhan-Song Xu

, Wan-Jia Qin

Chen-Jie Fei

and Jiong Chen

State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-

products, Ningbo University, Ningbo, Zhejiang, China,

Laboratory of Biochemistry and Molecular

Biology, School of Marine Sciences, Ningbo University, Ningbo, China,

Key Laboratory of Aquacultural

Biotechnology Ministry of Education, Ningbo University, Ningbo, China,

Li Dak Sum Yip Yio Chin

Kenneth Li Marine Biopharmaceutical Research Center, Department of Marine Pharmacy, College of

Food and Pharmaceutical Sciences, Ningbo University, Ningbo, China

Breast cancer (BC) is a kind of malignant cancer in women, and it has become

the most diagnosed cancer worldwide since 2020. Histone methylation is a

common biological epigenetic modiﬁcation mediating varieties of physiological

and pathological processes. Lysine-speciﬁc demethylase 1 (LSD1), a ﬁrst

identiﬁed histone demethylase, mediates the removal of methyl groups from

histones H3K4me1/2 and H3K9me1/2 and plays a crucial role in varieties of

cancer progression. It is also speciﬁcally ampliﬁed in breast cancer and

contributes to BC tumorigenesis and drug resistance via both demethylase

and non-demethylase manners. This review will provide insight into the

overview structure of LSD1, summarize its action mechanisms in BC,

describe the therapeutic potential of LSD1 inhibitors in BC, and prospect the

current opportunities and challenges of targeting LSD1 for BC therapy.

KEYWORDS

LSD1, histone demethylase, breast cancer, inhibitors, H3K4me1/2, H3K9me1/2

1 Introduction

Breast cancer (BC) is a kind of malignant tumour in women occurring in the breast

glandular epithelial tissues, and it has become the most diagnosed cancer worldwide since

2020 (Siegel et al., 2021;Siegel et al., 2022). The incidence of BC is increasing year by year

and patients are getting younger and younger, posing a serious threat to women’s health

(Siegel et al., 2022). Although advances in early diagnosis and treatment of BC have

partially alleviated the crisis of some BC patients, there are still a large number of patients

suffering from BC due to their complex pathogenesis, insensitivity to existing drugs, and

easy-to-develop drug resistance (Yang et al., 2019;Yang et al., 2021b). Therefore, there is

an urgent need to ﬁnd new and effective targeted therapies for this type of BC.

OPEN ACCESS

EDITED BY

Chao Han,

China Pharmaceutical University, China

REVIEWED BY

Haibing Zhou,

Wuhan University, China

Yingtang Zhou,

Zhejiang Ocean University, China

*CORRESPONDENCE

Jiong Chen,

jchen1975@163.com,

chenjiong@nbu.edu.cn

SPECIALTY SECTION

This article was submitted to

Pharmacology of Anti-Cancer Drugs,

a section of the journal

Frontiers in Pharmacology

RECEIVED 08 July 2022

ACCEPTED 15 August 2022

PUBLISHED 16 September 2022

CITATION

Yang G-J, Liu Y-J, Ding L-J, Tao F,

Zhu M-H, Shi Z-Y, Wen J-M, Niu M-Y,

Li X, Xu Z-S, Qin W-J, Fei C-J and

Chen J (2022), A state-of-the-art review

on LSD1 and its inhibitors in breast

cancer: Molecular mechanisms and

therapeutic signiﬁcance.

Front. Pharmacol. 13:989575.

doi: 10.3389/fphar.2022.989575

Wen, Niu, Li, Xu, Qin, Fei and Chen. This

is an open-access article distributed

under the terms of the Creative

Commons Attribution License (CC BY).

The use, distribution or reproduction in

other forums is permitted, provided the

original author(s) and the copyright

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original publication in this journal is

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or reproduction is permitted which does

not comply with these terms.

Frontiers in Pharmacology frontiersin.org01

TYPE Review

PUBLISHED 16 September 2022

DOI 10.3389/fphar.2022.989575

Lysine-speciﬁc demethylase 1 (LSD1) is a ﬂavin-dependent

lysine-speciﬁc histone demethylase ﬁrst identiﬁed in 2004 and

mediated transcriptional activation or repression via erasing

methyl groups from H3K9me2/1 and H3K4me2/1,

respectively (Figure 1)(Shi et al., 2004;Fang et al., 2020;Kim

et al., 2021;Malagraba et al., 2022;Song et al., 2022). Recently

studies found that LSD1 could also remove the methyl groups

from several non-histone proteins such as ERα, MTA1, HIF-1α,

AGO2, HSP90, MEFD2, and STAT3 and be involved in many

cancer cell events (Majello et al., 2019). LSD1 exhibits its catalytic

mechanism via consuming oxidation of FAD and O

and

yielding HCHO and H

in cellulo (Yang et al., 2018a).

Apart from demethylase activity, LSD1 exhibits non-

demethylase activity via interacting with its client proteins

and is involved in physiological and pathological processes

(Gu et al., 2020). LSD1 is also overexpressed in varieties of

cancers and mediates their progression (Yang et al., 2018a;

Fang et al., 2019;Fang et al., 2020). LSD1 is aberrantly

expressed in BC and promotes proliferation and metastasis of

BC cells (Liu et al., 2020a;Zhou et al., 2021a). Moreover,

LSD1 also is involved in regulating resistance of

chemotherapy and immunotherapy in BC (Kim et al., 2013;

Boulding et al., 2018;Yang et al., 2018d;Qin et al., 2019;Verigos

et al., 2019;Tu et al., 2020;Sobczak et al., 2022). Given the

multifaceted functions of LSD1 in BC progression, new

therapeutic strategies targeting LSD1 are constantly being

developed, such as the discovery of novel LSD1 inhibitors,

the development of dual-target inhibitors, and the

combination therapies with chemical agents or

immunomodulators (Kim et al., 2013;Boulding et al., 2018;

Yang et al., 2018d;Qin et al., 2019;Verigos et al., 2019;Tu

et al., 2020;Sobczak et al., 2022). Therefore, LSD1 is a potential

target for BC therapy.

Herein, the structures, functions and the regulatory roles of

LSD1 in tumorigenesis were introduced, the reported

LSD1 inhibitors and their therapeutic mechanisms for BC

treatment were summarized, and the current challenges and

the potential opportunities of LSD1 inhibitors for BC therapy

were prospected.

2 The overview of LSD1

2.1 The structure of LSD1

LSD1 is a FAD-dependent demethylase encoding a peptide

with 852 amino acid residues. LSD1 consists of highly conserved

three distinct domains: a SWI3/Rac8/Moira (SWIRM) domain, a

tower domain (TD), and a catalytic amine oxidase domain

(AOD) (Figures 1A,B)(Forneris et al., 2008;Yang et al.,

2018a). The SWIRM domain is an indispensable domain for

LSD1-mediated histone modiﬁcation and chromatin remodeling

(Metzger et al., 2005). The TD is a special domain with two

antiparallel helices, and it can bind to RCOR1 and form the

CoREST complex (Pilotto et al., 2015;Marabelli et al., 2016). The

AOD domain is the catalytic domain of LSD1, and it consists of

two well-deﬁned motifs: the substrate-recognition motif and the

FAD-binding motif (Yang et al., 2018a). The latter is highly

conserved and responsible for binding sites of some reported

LSD1 inhibitors. The two motifs assemble into a big cavity

containing the interface of enzyme activity centre (Forneris

et al., 2008). In the active state of LSD1, the second lobe of

the AOD domain could form a hydrophobic binding pocket

SWIRM domain (Yoneyama et al., 2007). This binding pocket

mediates LSD1 binding to histone H3 and is also chosen as the

binding pocket for developing LSD1 inhibitors (Zhou et al.,

2015).

2.2 The functions and regulations of LSD1

LSD1 plays heterogeneous roles via transcriptionally

modulating its downstream genes in demethylase-dependent or

-independent modesin varieties of cancers(Song et al., 2022;Yang

FIGURE 1

Structure and function of LSD1. (A) Distribution of domains of LSD1. (B) LSD1-mediated transcriptional modulation. (C) Overview structure of

LSD1.

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Yang et al. 10.3389/fphar.2022.989575

et al., 2022). It acts as an oncogene in some cancers, while

functioning as a cancer-suppressor gene in the other cancers

(Yang et al., 2018a;Hu et al., 2019). In addition, LSD1 is also

regulated by multiple epigenetic regulators in BC.

2.2.1 LSD1 as a transcription co-repressor

Upregulating of H3K4me2/1 often contributes to the

transcriptional activation (Figure 1C). LSD1 removes methyl

groups from active Histone 3 via assembling into different co-

repressor complexes with several distinct proteins and shaping

chromatin into a repressive conformation. For example,

LSD1 was found to form a co-repressor complex with SIN3A/

HDAC and maintain sensitivity to chemotherapy via reducing

inhibiting several genes such as TGFB2, CASP7, TERT,MDM2,

and HIF1αin BC (Yang et al., 2018d). It also could assemble into

LSD1/CoREST/BRMS1 and inhibit the metastasis of BC cells via

reduced levels of Vimentin,COL5A2,INSIG2,MRPL33,SLC1A1,

KLK11, and OLFML3 (Qiu et al., 2018).

2.2.2 LSD1 as a transcription co-activator

LSD1 also works as a transcriptional co-activator via

demethylating H3K9me2/1 (Figure 1C). It can promote

estrogen transcription in breast cancer cells through

interacting with estrogen receptor (ER) (Bennesch et al.,

2016). Additionally, LSD1 also regulates chromatin events

such as DNA replication, heterochromatin, and imprinting

propagation (Zhu et al., 2012;Yang et al., 2018a).

2.2.3 The epigenetic regulation of LSD1

The function of LSD1 has also been found to be regulated by

many epigenetic components. For example, miR-708 inhibits BC

proliferation and invasion via directly binding to the 3′UTR of

LSD1 and reducing its level (Ma et al., 2016). In addition,

epigenetic modiﬁcations such as phosphorylation (Peng et al.,

2015;Feng et al., 2016;Zhou et al., 2016), acetylation (Luo et al.,

2016), methylation (Liu et al., 2020a), and ubiquitination (Wu

et al., 2013;Yi et al., 2016;Zhou et al., 2016;Gong et al., 2021) also

contribute to the function of LSD1 (Figure 2). PKCαcan

phosphorylate LSD1 at S112, activating its demethylase

activity and enhancing the occupancy on E-cadherin

promoter, and ﬁnally promote EMT and metastasis in BC

(Feng et al., 2016). Phosphorylated modiﬁcation is also found

to regulate LSD1-medatied DNA damage (Peng et al., 2015). To

be speciﬁc, LSD1 was di-phosphorylated at S131 and S137 by

CK2 and Wip1, respectively, which promoted its interaction with

RNF168 and RNF168-dependent 53BP1 ubiquitination and

subsequent recruitment to the DNA damage sites. CK1αwas

also found to phosphorylate LSD1 at S687 and then induce

S683 phosphorylation of LSD1 by nuclear GSK3β(Zhou et al.,

2016). The di-phosphorylated LSD1 would be deubiquitylated by

USP22 and induced stabilization itself. MOF, a lysine

acetyltransferase ﬁrst found acetylated histone H4 at

K16 residue, also could catalyze the acetylation of LSD1 at

K432, K433, and K436 and suppress LSD1-medaited EMT in

epithelial cells (Luo et al., 2016). Arginine methyltransferase 4

(PRMT4) was also found to mediate deubiquitination and

stabilization of LSD1 via dimethylating it at R838 and

promoting its deubiquitination by USP7 (Liu et al., 2020a).

Apart from USP7 and USP22, USP28 also could remove

ubiquitin modiﬁcations from LSD1, maintain its stability, and

thus confer stemness to BC cells (Wu et al., 2013). Recently,

OTUD7B was also found to mediate deubiquitination of LSD1 at

K226/277 residues, which stabilized LSD1 and promoted its

assembly into co-repressor complex (Gong et al., 2021).

3 The role of LSD1 in breast cancer

3.1 Role of LSD1 in breast cancer

progression

LSD1 is overexpressed in several subtypes of BC and

functions as an oncogene mediating proliferation,

differentiation, invasion, and metastasis of BC cells (Figure 3;

Tables 1–3)(Ma et al., 2016;Feng et al., 2017;Yang et al., 2018a;

Hu et al., 2019;Zhou et al., 2021a;Ji et al., 2021). When normal

human mammary epithelial cells are exposed to carcinogens,

their LSD1 levels would be upregulated and promote the

carcinogenesis via reducing p57

kip2

level (Bradley et al., 2007).

LSD1 exhibits its oncogene functions via interacting with distinct

ligands in different BC subtypes. As a major biomarker of ER-

positive BC, ERαand its transcriptional activity are regulated by

LSD1 via assembling into complex with different ligands to

mediate BC proliferation (Lim et al., 2010;Pollock et al.,

2012;Zhu et al., 2012;Andresen et al., 2017). For example,

CAC1 antagonized LSD1-mediated ERαactivation and

suppressed the proliferation of BC cells (Kim et al., 2013),

while ASXL2 promoted proliferation of BC cells via forming a

complex ASXL2/LSD1/UTX/MLL to activate ERαactivity (Park

et al., 2016). In addition, LSD1 reduces tumor suppressor gene

Lefty1 via interacting with β-catenin in BC cells (Yakulov et al.,

2013), and suppresses BC cell growth through binding to histone

deacetylases (HDACs) (Huang et al., 2012;Vasilatos et al., 2013).

It also sensitizes BC cells to chemotherapy via assembling into a

complex with SIN3A/HDAC and inhibits BC proliferation and

metastasis via interacting with HDAC5 (Cao et al., 2017;Cao

et al., 2018;Yang et al., 2018d). Further studies found that

LSD1 promotes BC metastasis via H3K4me2 demethylase

occupying the gene promoters of Snail and Slug and reducing

their levels (Lin et al., 2010;Wu et al., 2012;Lin et al., 2014;

Phillips and Kuperwasser, 2014;Bai et al., 2017). Interestingly,

androgen receptor (AR) is also involved in BC metastasis via

interacting with LSD1 to reduce E-cadherin and upregulate

Vimentin (Feng et al., 2017).

Interestingly, LSD1 also exert its function as a tumor

suppressor gene via forming different complexes with distinct

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Yang et al. 10.3389/fphar.2022.989575

ligand proteins (Li et al., 2017). LSD1 was also found to inhibit

proliferation, invasion, and metastasis in vitro and in vivo via

assembling into LSD1/NuRD complex (Wang et al., 2009;Li

et al., 2017). This complex exhibits its heterogeneous tumor

suppressor functions dependent of the different subunits in

varieties of BC cells (Wang et al., 2009;Li et al., 2017). In

MCF-7 cells, zinc-ﬁnger protein 516 (ZNF516) inhibited

EGFR transcription, and thus reduced the proliferation and

invasion of BC in vitro and in vivo via targeting CtBP/LSD1/

CoREST complex (Li et al., 2017). Breast carcinoma metastasis

suppressor 1 (BRMS1) is another gene coordinating with LSD1/

NuRD complex to inhibit the metastasis of MCF7 cells (Qiu et al.,

2018). In MDA-MB-231 cells, LSD1/NuRD complex suppressed

BC tumorigenesis and metastasis via recruiting the homeotic

protein SIX3 (Zheng et al., 2018). CC chemokine ligand 14

(CCL14) is a chemokine promoting angiogenesis in viral

infection and tumor progression (Mortier et al., 2008;Li et al.,

2011). KDM5B reduce CCL14 transcription to impede metastasis

via targeting LSD1/NuRD complex (Li et al., 2011). In addition,

in luminal BC, LSD1 suppressed invasion, migration, and

metastasis BC cells via raising GATA3 and repressing

TRIM37 (Hu et al., 2019).

Apart from as a subunit of many complexes mediating BC

progression, the function of LSD1 was also regulated by several

epigenetic enzymes in BC (Feng et al., 2016;Liu et al., 2020a;

Gong et al., 2021). Feng et al. (2016) highlighted the PKCα-

mediated phosphorylation of the S112 residue of LSD1 which

was crucial for epithelial-mesenchymal transition (EMT) and

FIGURE 2

Residue sites were modiﬁed by varieties of posttranslational modiﬁcations in LSD1.

FIGURE 3

Role of LSD1 in breast cancer progression, angiogenesis, tumor microenvironment, and drug resistance.

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metastasis of BC cells. Liu et al. (2020a) found that

PRMT4 methylated and stabilized LSD1 via promoting it and

it binding to deubiquitinase USP7 in BC cells. Recently, Gong

et al. (2021) revealed that OTUD7B could remove the Poly-Ub

Chains of LSD1 at K226/277 residues, maintain the integrity of

LSD1/CoREST/HDACs co-repressor complexes, and inhibit BC

metastasis.

3.2 Role of LSD1 in tumor angiogenesis

Angiogenesis is a pivotal process for BC growth and metastasis

(Ayoub et al., 2022). LSD1 is also involved in this process via

modulating several pathways (Table 2)(Li et al., 2011;Lee et al.,

2017). Li et al. (2011) found that LSD1 worked as a co-repressor and

suppressed angiogenesis and metastasis of BC cells via assembling

TABLE 1 Roles of LSD1 in BC progression.

Substrates Complexes/

pathways

Target genes Functions References

H3K4me2/me1 —p57kip2 Promoting BC initiation Bradley et al. (2007)

H3K4me2/me1 CAC1/LSD1/ERαERα-target genes Inhibiting proliferation Kim et al. (2013)

H3K9me2/me1 ASXL2/LSD1/UTX/

MLL2

ERαPromoting proliferation Park et al. (2016)

H3K4me2/1 LSD1/β-catenin Lefty1 Promoting proliferation Yakulov et al. (2013)

H3K4me2/1 LSD1/SIN3A/HDAC CASP7, TGFB2, CDKN1A(p21), HIF1A,

TERT, and MDM

Sensitizing BC cells to

chemotherapy

Yang et al. (2018d)

H3K4me1/me2 LSD1/HDAC5 p21 and CLDN7 Hindering BC proliferation and

invasion

Cao et al. (2017),Cao et al. (2018)

H3K4me2 Snail E-cadherin, PTEN Promoting EMT Lin et al., 2010,Lin et al. (2014)

H3K4me2 Slug BRCA1, ESR1 Inhibiting invasion Bai et al., (2017),Phillips and

Kuperwasser, (2014)

H3K9me2, H3K4me2 AR E-cadherin and Vimentin Promoting progression and

metastasis

Feng et al. (2017)

H3K4me2 LSD1/CoREST IGF1R, RHOA, and TGFB1 Inhibiting metastasis Wang et al. (2009)

H3K4me2 ZNF516/CtBP/LSD1/

CoREST

EGFR Inhibiting proliferation and

metastasis

Li et al. (2017)

H3K4me1/me2 BRMS1/LSD1/CoREST Vimentin Suppressing metastasis and

invasion

Qiu et al. (2018)

H3K4me1/me2 LSD1/NuRD/SIX3 WNT1 and FOXC2 Zheng et al. (2018)

H3K4me2, H3K4me3 LSD1/NuRD/KDM5B CCL14 Li et al. (2011)

H3K4me2 LSD1/GATA3 GATA3,TRIM37 Hu et al. (2019)

H3K4me1/me2,

H3K9me2

OTUD7B/LSD1 Snail, CDK6, ... Promoting metastasis Gong et al. (2021)

H3K4me1/me2 PKCα/LSD1 E-cadherin Promoting EMT and metastasis Feng et al. (2016)

H3K4me1/me2 PRMT4/LSD1/USP7 E-cadherin and Vimentin Promoting invasion and

metastasis

Liu et al. (2020a)

TABLE 2 Regulatory roles of LSD1 in BC angiogenesis and microenvironment.

Substrates Ligand

proteins

Complexes/

pathways

Target genes Functions References

HIFαK391 NuRD LSD1/NuRD VEGF Promoting angiogenesis Lee et al. (2017)

H3K4me2,

H3K4me3

KDM5B and

NuRD

KDM5B/LSD1/

NuRD

CCL14 Suppressing angiogenesis Li et al. (2011)

H3K4me2/1 PKC-θLSD1S111/PKC-θJUNB, KLF10, KLF6,

and CCL2

Promoting mesenchymal and stem-like signature,

and reducing M1 macrophage

Boulding et al. (2018)

H3K4me2 —— CCL5, CXCL -9, -10,

and PD-L1

Reducing CD8

T cell inﬁltration Bennani-Baiti, (2012),Shen

et al. (2022)

H3K4me2,

H3K9me2

CoREST LSD1/CoREST Macrophage

polarization genes

Inhibiting Mvtoward a M1-like phenotype in

the TME

Benedetti et al. (2019)

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Yang et al. 10.3389/fphar.2022.989575

into a complex with KDM5B and NuRD and reducing the

transcription of CCL4. Hypoxia-inducible factor alpha (HIF1α),

a transcription factor promoting breast cancer angiogenesis, is also

found to be regulated by LSD1/NuRD complex. To be speciﬁc, this

complex demethylated HIF1αto stabilize it, and then stabilized

HIF1αwould upregulate the vascular endothelial growth factor

(VEGF) via cooperating with CBP and metastasis-associated

antigen 1, and induce angiogenesis in BC (Lee et al., 2017).

3.3 Role of LSD1 in the breast cancer

microenvironment

Tumor microenvironment refers to the internal and external

environment of tumor cells where they survive, grow, and

metastasize (Xiao and Yu, 2021). Tumor stroma consists of

several heterogeneous cells such as cancer-associated

ﬁbroblasts (CAFs) and macrophages (Mv), which promote

tumorigenesis via the secretion of varieties of chemokines,

cytokines, and growth factors (Disis, 2010). While

LSD1 increases CAF burden and reducing innate M1 Mv

inﬁltration at the primary tumor site in BC (Boulding et al.,

2018). In TNBC, LSD1 also mediated CD8

lymphocyte

trafﬁcking to the tumor microenvironment and reducing Mv

polarization toward M1-like phenotype (Qin et al., 2019;Tan

et al., 2019;Shen et al., 2022).

3.4 Role of LSD1 in drug resistance of

breast cancer

Drug resistance is one of the major causes that leads to

distant metastasis, poor prognosis, and death of BC (Wen et al.,

2020). LSD1 is widely involved in the resistance to chemotherapy

(Kim et al., 2013;Boulding et al., 2018;Verigos et al., 2019;

Sobczak et al., 2022), hormone therapy (Bennani-Baiti, 2012;

Cortez et al., 2012;Benedetti et al., 2019;Sukocheva et al., 2020),

immunotherapy (Qin et al., 2019;Tu et al., 2020), and targeted

therapy (Strachowska et al., 2021;Liu et al., 2022)ofBC(Table 3).

Brieﬂy, LSD1 promotes chemoresistance via functioning as a co-

activator through interacting with different ligand proteins (Kim

et al., 2013;Boulding et al., 2018;Verigos et al., 2019;

Strachowska et al., 2021). It mediates resistance to hormone

therapy via activating ER transcriptional activity (Cortez et al.,

2012;Benedetti et al., 2019). In addition, LSD1 is also involved in

resistance to PD-1 antibody treatment and BRD4 inhibitors via

its transcriptional inhibitory activity against multiple oncogenes

(Qin et al., 2019;Tu et al., 2020;Liu et al., 2022).

4 Targeting LSD1 for breast cancer

therapy

Considering the crucial roles of LSD1 in BC progression, it

has the potential as a therapeutic target for BC treatment.

Currently, tens of LSD1 inhibitors have been documented

with anti-BC activity with some of these having entered

clinical trials. Herein, they were classiﬁed into seven

subcategories based on their structural characteristics: PCPA-

based LSD1 inhibitors, polyamine analogues, natural products,

propargylamine derivatives, benzohydrazide derivatives, phenyl

oxazole derivatives, and dual-target inhibitors.

4.1 PCPA-based LSD1 inhibitors

Since LSD1 and monoamine oxidases (MAOs) share high

similarity in their catalytic domains, several LSD1 inhibitors have

TABLE 3 Roles of LSD1 in drug resistance of BC.

Resistant agents Complexes/

pathways

Target genes Functions References

Chemotherapy Paclitaxel CAC1/LSD1/ER TFF1, TERB Promoting paclitaxel Kim et al. (2013)

LSD1S111/PKC-θJUNB,KLF10,KLF6,

and CCL2

Resistance Boulding et al. (2018)

Doxorubicin —— Enhancing BC stemness Verigos et al. (2019)

Doxorubicin, cisplatin,

daunorubicin, and methotrexate

CBP/LSD1 ABCC1 and ABCC10 Promoting drug efﬂux Strachowska et al., (2021);

Sobczak et al., (2022)

Hormone

therapy

Tamoxifen LSD1/PELP1/ER GREB1C,Aromatase Promoting BC hormone resistance Cortez et al. (2012)

LSD1/ER ER Activating ER transcriptional activity Benedetti et al. (2019)

Immunotherapy PD-1 antibody —CCL5,CXCL9,

CXCL10, and PD-L1

Reducing efﬁcacy of PD-1 antibody Qin et al. (2019)

EOMES/LSD1 Mvpolarization

genes

Reducing immune Cell inﬁltration

and increasing checkpoint markers

Qin et al., (2019);Tu et al.,

(2020)

Targeted therapy BRD4 inhibitors BRD4/LSD1/NuRD GNA13 and PDPK1 Promoting JQ1 resistance Liu et al. (2022)

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Yang et al. 10.3389/fphar.2022.989575

been discovered based on reported MAO inhibitors via in silicon

screening and chemical structure optimizations (Yang et al.,

2007;Yang et al., 2018a). Tranylcypromine hydrochloride (2-

PCPA, 1), an irreversible monoamine oxidase (MAO) inhibitor

with half maximal inhibitory concentration (IC

) of 11.5 and

7.0 μM for MAO A and MAO B in vitro, respectively, has also

exhibited inhibitory activity against LSD1 (IC

= 22.3 μM)

(Figure 4)via covalently binding to its FAD-binding motif (Ji

et al., 2017;Cao et al., 2018). Further study veriﬁed that

compound 1also inhibited migration, invasion, and metastasis

of TNBC cell lines BT-549 and MDA-MB-231 cells and tumor

bone metastasis in vivo. In the mechanism, 1blocked the

interaction between LSD1 and slug, and thus upregulated

suppressor E-cadherin and reduced epithelial markers

(Ferrari-Amorotti et al., 2014).To improve the potency, and

selectivity of 2-PCPA, some 2-PCPA derivatives have been

designed and synthesized based on multiple optimization

strategies. GlaxoSmithKline lnc. has designed 2 PCPA-based

LSD1 inhibitors 2and 3with IC

of 1.7 μM, and 0.016 μM,

respectively, (Figure 4)(Tu et al., 2020;Zhou et al., 2021b).

N-alkylated 2-PCPA derivative 2, a selective and orally bioavailable

for LSD1 inhibitor induced IFN-γ/TNF-α-expressing CD8 T cell

inﬁltration into the tumors of 4T1 immunotherapy-resistant mice

and sensitized to immunotherapy via aLSD1-EOMESswitch.

Interestingly, 2 showed much potent anti-BC activity than PD-L1

antibody (Tu et al., 2020). Compound 3promoted the antigen

presentation and enhanced the tumor-killing activity of tumor-

speciﬁc cytotoxic T-cells in 4T1 mouse model (Zhou et al., 2021b).

Compounds 4and 5(Figure 4) are two PCPA-4-hydroxytamoxifen

conjugates, which released 4-hydroxytamoxifen catalyzing by

LSD1 in vitro and in cellulo and exhibited anti-proliferative

activity against MCF-7 cells at concentrations as low as 0.1 μM.

In addition, both of the two conjugates have better in cellulo anti-

proliferative activity than their parent compounds (Ota et al., 2016).

NCD38 (6), a selective LSD1 inactivator optimized from PCPA with

of 0.59 μM(Sugino et al., 2017), could reduce the stemness of

TNBC cells and tumor growth in vitro (Zhou et al., 2021a). ORY-

1001 (7), a PCPA derivative in phase II clinical trial for acute

myelocytic leukemia, could inhibit TNBC cells and HER2-positive

BC cells in distinct mechanisms (Figure 4)(Cuyàs et al., 2020;Wang

et al., 2022). Compound 7inhibited HER2-positive BC via reducing

SOX2-driven breast cancer stem cells. In the mechanism, compound

7disturbed the assembly between LSD1 and co-repressor RCOR1/

CoREST via blocking the binding between LSD1 and FAD cofactor,

and thus enhanced transcriptional repression of SOX2 (Cuyàs et al.,

2020). In TNBC, compound 7suppressed the proliferation of TNBC

cells via devitalizing androgen receptor (Wang et al., 2022).

4.2 Polyamine analogues

Polyamine analogues, previously identiﬁed as the FAD-

dependent spermine oxidase inhibitors, were also found to

inhibit LSD1 demethylase activity in 2007 (Huang et al.,

2007). Bisguanidine 8and biguanide 9exhibited demethylase

inhibitory activity by over 50% at 1 μM but both of them lack

selectivity among MAOs (Nowotarski et al., 2015). Four (bis)-

thioureidopropyldiamine compounds (10–13) showed improved

selectivity compared with their lead compounds 8and 9

(Figure 5). Among them,compound 13 exhibited the best

selectivity and potency with IC

values of 5.0 and 4.8 μM

in vitro, respectively. In fact, 13 also showed much more

potent anticancer activity against MCF7 cells than 2-PCPA

(Nowotarski et al., 2015). Further study showed that

compounds 10–13 suppressed the proliferation of MCF-7 cells

via increasing H3K4me2 levels, which signiﬁcantly upregulated

tumor suppressor genes p16,GATA4,HCAD, and SFRP2. The

docking assay indicated that 11 could form three hydrogen bonds

with residues N535 and A539, and FAD within the LSD catalytic

pocket. In addition, the hydrophobic interactions between

hydrophobic residues in lining the LSD1 pocket and 11 also

contributed to their binding ability.

4.3 Natural products

Natural products are one of the major sources in drug

discovery due to their diverse chemical scaffolds and activity

proﬁles (Fang et al., 2020;Yang et al., 2020;Yang et al., 2021a;

Cheng et al., 2022b;Song et al., 2022). Many natural products and

their derivatives have been found with in vitro inhibitory activity

against LSD1.

Kong’s group identiﬁed six ﬂavonoid compounds (Figure 6,

14–19) with inhibitory activity against LSD1 from Scutellaria

baicalensis Georgi using countercurrent chromatography (CCC)

(Han et al., 2018). Among them, compound 19 is the best

LSD1 inhibitor with the in vitro IC

of 2.98 µM and in

cellulo IC

of 17.94 µM against MDA-MB-231 cells.

Isoquercitrin (Figure 6,20), a ﬂavonoid compound with anti-

BC activity extracted from Bidens bipinnata L,isan

LSD1 inhibitor that inhibited proliferation of TNBC cell line

MDA-MB-231 via activating mitochondrial-mediated apoptosis

(Xu et al., 2019). Biochanin A (21), a dietary ﬂavonoid from Cicer

arietinum L, could inhibit the proliferation and metastasis of BC

in cellulo and in vivo (Moon et al., 2008;Sehdev et al., 2009;Ren

et al., 2018). Compound 21 was found to be effective and

reversible with IC

of 2.95 μM and it preferably suppressed

LSD1 over MAO-A/B (>32 μM) (Wang et al., 2020). In gastric

MGC-803 cells, Biochanin A induced the accumulation of

H3K4me1/2 and inhibited cell growth moderately (IC

6.77 µM) (Wang et al., 2020). Oleacein (Figure 5,22), a

dihydroxy-phenol found in extra virgin olive oil, is a FAD

competitive LSD1 inhibitor with IC

of 2.5 μMin vitro

(Cuyàs et al., 2019). Compound 22 reduced the stemness of

BC stem cells via blocking the interaction between LSD1 and the

methylated histone H3, disintegrating the assembled co-

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Yang et al. 10.3389/fphar.2022.989575

FIGURE 4

Chemical structures of PCPA-based LSD1 inhibitors in BC therapy.

FIGURE 5

Chemical structures of polyamine analogue-based LSD1 inhibitors.

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Yang et al. 10.3389/fphar.2022.989575

repressor complex LSD1/RCOR1/CoREST, disturbing the

occupation of LSD1 to the SOX2 promoter and ﬁnally

reducing the SOX2 level. Capsaicin (Figure 6,23), a bioactive

compound from chili peppers with the broad spectrum of

anticancer activity in various subtype of BC cells (Chou et al.,

2009;Thoennissen et al., 2010;Wu et al., 2020;Chen et al., 2021),

was found to act as reversible LSD1 inhibitor with an IC

value

of 0.6 μM(Jia et al., 2020). Compound 23 competitively occupied

with FAD-binding sites within the catalytic pocket of LSD1,

raised H3K4me1/2 levels and suppressed the proliferation and

migration of BC cells.

The dried root of Salvia miltiorrhiza is a traditional Chinese

medicine used for over 1,000 years to treat cardiovascular and

cerebrovascular diseases, gynecological diseases, diabetes, and

insomnia (Su et al., 2015;Jia et al., 2019;Shi et al., 2019). S.

miltiorrhiza has also been reported to improve the survival rate of

BC patients and several bioactive components (Figure 6,24–29)

mediated its pharmacological actions via multiple anticancer

FIGURE 6

Structure of natural LSD1 inhibitors.

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pathways (Jin et al., 2021;Mahmoud et al., 2021). For example,

rosmarinic acid (24) could suppress proliferation, metastasis and

angiogenesis, and sensitize BC cells to paclitaxel via NF-κB-

p53 pathways (Mahmoud et al., 2021). Dihydroisotanshinone I

(25) inhibited the proliferation of BC cells via inducing their

ferroptosis and apoptosis (Lin et al., 2019). Cryptotanshinone

(26) inhibited migration through inactivating PKM2/β-Catenin

signaling, and mediated drug resistance via reducing the

oligomer formation of breast cancer resistance protein on the

cell membrane, and thus blocking its efﬂux function (Zhou et al.,

2020;Ni et al., 2021). Tanshinone I (27) inhibited the

proliferation of MDA-MB-231 cells via activating the AMP-

activated protein kinase mediating autophagic signaling (Zheng

et al., 2020). Tanshinone IIA (28) sensitized BC cells to

adriamycin via attenuates the stemness of BC cells by

targeting the miR-125b/STARD13 signaling (Li et al., 2022).

Recently, the six extracted monomeric compounds from roots

of S. miltiorrhiza have been identiﬁed as LSD1 inhibitors with

their IC

values within the range 0.11–20.93 μM(Lin et al.,

2020). Among them, salvianolic acid B (29) showed the best

inhibitory activity against LSD1 (IC

= 0.11 μM) and it

demethylase-dependently inhibited the proliferation and

migration of MDA-MB-231 cells with an IC

value of

54.98 μM at 24 h against MDA-MB-231 cells.

Coptis chinensis, another traditional Chinese medicine widely

used over 2,000 years for treatment of atherosclerosis, diabetes,

and inﬂammation (Alami et al., 2020) has also been used to treat

a varieties of cancers including BC (Wu et al., 2019), and

isoquinoline alkaloids (Figure 6,30–34) have been identiﬁed

as the main anticancer active components of C. chinensis with

inhibitory activity against LSD1 (Yi et al., 2016). Epierberine (30)

inhibited the proliferation and metastasis of BC cells via induced

cell cycle arrest and induced apoptosis by regulating Wnt/β-

catenin pathway (Dian et al., 2022). Jatrorrhizine (32) exhibited

anti-proliferative activity via attenuating TNIK/Wnt/β-catenin

signaling in BC cells with IC

values of 11.08, 17.11, and

22.14 μM against MCF-7, MDA-MB-231, and 4T1 cells,

respectively (Sun et al., 2019). Berberine (27) sensitized the

BC cells to chemotherapeutic agents via reducing XRCC1-

mediated base excision repair (Gao et al., 2019). Palmatine

(34) reduced the lung metastasis of TNBC via downregulating

metastasis-associated protein 1 (MTA1) and increasing p53 level

(Ativui et al., 2022). Recently, Li Z. R. et al. (2020) found that ﬁve

protoberberine alkaloids (30–34) also showed the inhibitory

activities against LSD1. All the IC

values of them were as

low as micromoles and highly selective to LSD1 over MAOs.

Recently, Ren et al. (2021) also identiﬁed four

sesquiterpene-based LSD1 inhibitors (compounds 35–38)

with their IC

values within the range 3.97–22.22 μMfrom

zedoary turmeric oil using CCC strategy. Compound 36 had the

best inhibitory activity (IC

=3.95μM) of them and also

exhibited the anti-metastasis activity against MDA-MB-

231 cells.

4.4 Propargylamine derivatives

Due to the similar structure between MAOs and LSD1, two

MAOs inhibitors (Figure 7,39 and 40) with active

propargylamine group also showed a weak inhibitory activity

against LSD1 in the millimolar range (Lee et al., 2006;Matos

et al., 2009). To improve the potency of LSD1 inhibitor, a

covalent and irreversible LSD1 inhibitor (41) was designed

through combining the active propargylamine group with

N-terminal 21 amino acids of LSD1 substrate H3, compound

41 selectively inhibited LSD1 demethylase activity with a Ki value

of 0.107 μM(Culhane et al., 2006). Based on the structure of 41,

Schmitt et al. (2013) designed and synthesized a set of with

propargyl warhead (Figure 7,42–45). Among them, compound

44 was the best LSD1 irreversible inhibitor with IC

of 44.0 μM

in vitro, while 43 has the best anti-proliferative activity against

MCF7 cells (IC

= 91.5 μM) for 24 h (Schmitt et al., 2013). The

docking analysis of the binding mode between 42 and

LSD1 showed that residues Y761 and D555 formed hydrogen

bonds with the amine of N-propargylamine warhead and the

amide nitrogen atom of the benzamide moiety, respectively. The

aromatic substituents extensively form hydrophobic and

T-shaped aromatic interactions with F558, F560, Y807,

and H812.

4.5 Benzohydrazide derivatives

Sorna et al. (2013) identiﬁed six benzohydrazides (Figure 8,

46–51)IC

values within 0.19–0.333 μM range based on virtual

screening from a compound library containing

2,000,000 compounds and biochemical assay. Then, three

compounds 53–55, with IC

of 0.128, 0.013, and 0.014 μM,

respectively, were gotten though structure-based optimization.

Compound 55, the best potent LSD1 inhibitor of them, is

reversible and speciﬁc for LSD1 and inhibits the proliferation

and survival of seven BC cell lines with IC

from 0.468 to

2.730 μM range, which is more potent than a known MAO

inhibitor 2-PCPA. Further study showed that 55 suppressed

the proliferation of BC cells via reducing Sox2 expression,

promoting G1 cell cycle arrest, and inducing the expression of

differentiation-related genes in demethylase-dependent manner

(Zhang et al., 2013). The binding mode analysis using ICM

software showed that 55 could form three H-bonding

interactions with the residues G314, R350, and Y510 via its

benzohydrazide scaffold.

4.6 Phenyl oxazole derivatives

The polyamine/guanidine and methionine were often key

pharmacophores for designing MAOs inhibitors. Dulla et al.

designed a series of compounds (Figure 9,56–59) with related

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Yang et al. 10.3389/fphar.2022.989575

FIGURE 7

Structure of propargylamine-based LSD1 inhibitors.

FIGURE 8

Structure of benzohydrazide-based LSD1 inhibitors.

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Yang et al. 10.3389/fphar.2022.989575

pharmacophores using oxazole as a linker (Dulla et al., 2013).

The results showed that compounds 56–58 exhibited good

in vitro inhibitory activity against LSD1 with IC

of 16.1,

10.1, and 9.5 μM, respectively. Interestingly, all the synthesized

compounds including compound 59 showed an excellent

cytotoxicity activity against MDA-MB-231 cells (IC

1.035–1.328 nM) in cellulo, which suggested these compounds

have other targets contributing their anticancer activity. Docking

analysis showed that the free -NH2 and the oxazole nitrogen of

compound 56 formed H-bonding with residues T624 and

R316 of LSD1, respectively, and its oxazole ring is involved in

aπ-cation interaction with residue R316. In case of 57, its free

-NH2 formed a H-bond with S760, the sulfur atom formed

H-bond with M332 and V333, and the phenyl ring interacted

with W751 and Y761 residues via π-πstacking. In case of 57, its

replaced guanidine group could form two H-bonds with residues

E308 and R310 whereas its phenyl ring interacted with R316 via

π-cation interaction.

4.7 Dual-target inhibitors and combined

therapy

In BC, LSD1 and KDM6A have been found to co-express and

co-localize with ER, and regulate hormone receptor signaling

(Benedetti et al., 2019), suggesting that developing dual-targeting

agents against the two proteins are potent strategy to improve the

potency of LSD1 inhibitors. Based on this hypothesis, Altucci’s

group designed four dual-KDM inhibitors (Figure 10,60–63)

targeting LSD1 and KDM6A. Among them, compound 61

exhibited the best anti-BC activity with no signiﬁcant toxicity

and good oral potency. In the mechanism, 61 induced cell arrest

and apoptosis of hormone-positive BC in cellulo and in vivo and

exhibited lower toxicity against non-cancerous cells (HaCaT)

compared with clinical HDAC inhibitor Vorinostat.

Additionally, it also reduced the resistance to endocrine

therapies, suggesting dual-target is a feasible and potent

strategy to overcome drug resistance for BC therapy.

Compound 64 was identiﬁed as a non-covalent dual LSD1/

G9a inhibitor with anti-leukemia activity (Speranzini et al., 2016;

Menna et al., 2022). Mai’s group optimized the structure of 64 via

modifying its quinazoline core and got two non-covalent, and

more potent LSD1/G9a inhibitors (Figure 10,65 and 66).

Compared to lead compound 63, compounds 65 and 66

exhibited a better inhibitory activity against LSD1 but reduced

the inhibitory activity against G9a. Further study showed that 65

and 66 showed better anticancer activity against MDA-MBA-

231, THP-1, and MV4-11 cells without signiﬁcant toxicity to

non-cancer AHH-1 cells compared with epigenetic drug

UNC0638, which suggested that the LSD1 antagonistic activity

of LSD1/G9a inhibitors endorsed with anticancer activity

(Menna et al., 2022).

LSD1 has been found to promote BC proliferation via

interacting with histone deacetylases (HDACs) (Cao et al.,

2017). Huang’s group found that HDAC inhibitor

sulforaphane suppressed the proliferation of BC cells via

blocking activity of upstream transcription factor 1 (USF1) and

promoting ubiquitination degradation of LSD1, and LSD1 inhibitor

signiﬁcantly sensitized sulforaphane to BC in cellulo and in vivo

(Cao et al., 2018), which inhibited that the combined therapy or

discovery of LSD1/HDAC5 inhibitors is a potential strategy for BC

treatment. Zylla et al. (2022) study found that HDAC/

LSD1 inhibitor 67 (Figure 10) exhibited anti-proliferative and

anti-metastatic activity against TNBC in cellulo and in vivo.

Currently, hormonal drugs and chemotherapy have been

widely combined in the utilization for BC therapy in clinic. But

combined strategies also showed undeniable disadvantages

during clinic use. To overcome this phenomenon, Zhou’s

group developed a set of dual-target inhibitors based

compound 68. Among these conjugators, compound 69 has

FIGURE 9

Structure of phenyl oxazole-based LSD1 inhibitors.

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Yang et al. 10.3389/fphar.2022.989575

the best in vitro and in cellulo activity with IC

values of 9.67,

1.36, 1.55, and 8.79 μM against ERα,ERβ, LSD1, and MCF7,

respectively (He et al., 2020). Most notably, 69 exhibited better

anti-BC activity in MCF-7 cells than clinical agent 4-

hydroxytamoxifen.

5 Discussion and future prospects

Mounting evidence supports that LSD1 is overexpressed in

many subtypes of BC and promotes their proliferation (Pollock

et al., 2012;Yang et al., 2018d;Xu et al., 2019;Wang et al., 2022),

differentiation (Wu et al., 2013;Zhang et al., 2013;Ji et al., 2021),

metastasis (Li et al., 2011;Qiu et al., 2018;Zheng et al., 2018;Hu

et al., 2019;Gong et al., 2021), and drug resistance (Bennani-

Baiti, 2012;Verigos et al., 2019;Zhou et al., 2021a;Liu et al.,

2022), which makes LSD1 become a promising target for BC

therapy. But the detailed mechanisms of the LSD1 in BC

progression are unclear and more potential anti-tumor

pathways or downstream genes are yet to clarify due to the

heterogeneity of varieties of BC subtypes. For example, metastasis

and drug resistance are two main factors responsible for BC-

caused death in clinic (Cheng et al., 2021;Cheng et al., 2022a).

Although there are several reported researches on the roles of

LSD1 in BC metastasis and drug resistance, the speciﬁc functions

of LSD1 in these two cancer cell events are yet to be investigated.

In addition, many studies showed that LSD1 functioned as an

oncogene or suppressor gene in BC progression dependent on its

transcriptional regulatory activity via assembling into different

complexes with its client proteins. Therefore, mapping the

protein-protein interactome of LSD1 is a potential strategy to

further clarify its function in BC development (Yatim et al., 2012;

Yang et al., 2022). Meanwhile, the exploration on the functions of

LSD1 in homeostasis is also imperative to avoid the potential

health risks during the development and advancement of clinical

trials of LSD1 inhibitors. Moreover, most of the current studies

about LSD1 functions mainly focus on its histone demethylase

activity, and few works are available about the roles of non-

histone substrates, epigenetic modiﬁcations, and non-enzyme

activity of LSD1 in BC progression (Feng et al., 2016;Liu et al.,

FIGURE 10

Structure of reported dual-target inhibitors.

RBA values = ICE2

50 /ICCompound

50 × 100 ± the range (RBA value of E2 as 100%).

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Yang et al. 10.3389/fphar.2022.989575

2020a;Gong et al., 2021). Thus, it is imperative to further carry

out research in these areas.

Currently, some LSD1 inhibitors have entered clinical trials

to combat small lung cancer cells and acute myeloid leukemia

and several of them showed encouraging results (Fang et al.,

2019). But there is no LSD1 inhibitor in clinical trials for BC.

Many factors contribute to this phenomenon apart from the

complex etiological factor of BC. First, most of the reported

LSD1 inhibitors have poor selectivity, which adds to the

uncertainty of drug therapy. Second, some LSD1 inhibitors

such as compounds 56–59 exhibited intracellular activity

inconsistent with their inhibitory activity against demethylase

activity (Dulla et al., 2013), which suggested that there are

potential off-target effects and unpredictable risks of some

identiﬁed LSD1 inhibitors, when they were advanced into

clinical trials for BC therapy. Third, like other enzyme

inhibitors (Yang et al., 2018c;Wu et al., 2018;Yang et al.,

2019;Yang et al., 2021c;Yang et al., 2021d), most of the

reported LSD1 inhibitors were only detected in anti-BC

activity in vitro or in cellulo assays with a dearth of the

studies about in vivo toxicology, pharmacokinetics, and

effectiveness in animals. Finally, due to the existence of

several alternative signaling and isoenzymes in BC cells,

LSD1 inhibitor used alone may be not sufﬁcient to achieve

the desired therapeutic effect sometimes. To solve these

dilemmas, pharmaceutical chemists and pharmacologists have

proposed several strategies. Given allosteric regulation is a

common characteristic for metabolic enzymes (Kremer and

Lyssiotis, 2022), identifying allosteric pockets or sites and

developing corresponding inhibitors is a feasible strategy for

the discovery of LSD1 inhibitors. Targeting the protein–protein

interaction (PPI) is also an effective method to improve the

selectivity of enzymes (Yang et al., 2018a;Cheng et al., 2020;Yang

et al., 2021a;Yang et al., 2021c;Yang et al., 2021d;Yang et al.,

2022), blocking the interaction between LSD1 and its client

proteins may be also a useful strategy to develop selective

LSD1 inhibitors. Metal complexes have showed promising in

vivo activity for BC treatment (Yang et al., 2018b;Cheng et al.,

2022b), and Yang et al. (2017) have also identiﬁed a rhodium-

based LSD1 inhibitor with in cellulo anticancer activity against

prostate cancer, which suggested this kind of compound is a

unique source for the discovery of potent and selective

LSD1 inhibitors against BC treatment. Several drug design

strategy such as computer aided drug optimization and

proteolysis targeting chimera (PROTAC)-strategy have been

introduced to discover lead compounds against LSD1 with

better biocompatibility and in vivo potency (Liu et al., 2020b;

Martín-Acosta and Xiao, 2021). Moreover, combined therapy

and developing dual-target inhibitors have also been used to

improve the anticancer potency and overcome drug resistance of

LSD1 inhibitors (Ota et al., 2016;Cao et al., 2018;Benedetti et al.,

2019;Qin et al., 2019;Verigos et al., 2019;Liu et al., 2022). Drug

delivery by nanocarriers is a potent strategy to increase drug

utilization rate, improve potency, and reduce toxicity and drug

resistance of single agent or combined therapy (Singh and

Mitragotri, 2020;Vallet-Regí et al., 2022). LSD1 has been

found to exhibit its activity by promoting gastric cancer cell

stemness via delivered by endogenous small extracellular vesicles

in vivo (Zhao et al., 2021), and the drug delivery of LSD1 siRNA

using nanocarriers has exhibited potent anticancer activities in

several studies (Suzuki, 2019;Li B. et al., 2020;Jiang et al., 2021).

In a word, LSD1 plays a crucial role in BC progression and

drug resistance, and its inhibition is a potential anti-BC strategy

due to its efﬁcacy in current preclinical studies. Therefore, the

discovery of more speciﬁc LSD1 inhibitors is imperative to

deepen our understanding of the role of LSD1 in BC

tumorigenesis and verify the feasibility of targeting LSD1 as

an anti-BC therapy in clinic.

Author contributions

G-JY and JC: supervision, funding acquisition, and

writing—original draft preparation. Y-JL, L-JD, FT, M-HZ,

and Z-YS: preparation of ﬁgures and tables. J-MW, M-YN,

XL, Z-SL, W-JQ, and C-JF: investigation and validation,

writing, reviewing, and editing. G-JY and JC: conception,

writing, reviewing ,and editing. The authors contributed to the

data preparation and drafted and revised the manuscript.

Funding

This work was supported by the National Natural Science

Foundation of China (31972821), the General ScientiﬁcResearch

Project of Education of Zhejiang Province (Y202147351), the Starting

Research Fund of Ningbo University (421912073), and the State Key

Laboratory for Managing Biotic and Chemical Threats to the Quality

and Safety of Agro-products (2010DS700124-ZZ2008).

Conﬂict of interest

The authors declare that the research was conducted in the

absence of any commercial or ﬁnancial relationships that could

be construed as a potential conﬂict of interest.

Publisher’s note

All claims expressed in this article are solely those of the

authors and do not necessarily represent those of their afﬁliated

organizations, or those of the publisher, the editors, and the

reviewers. Any product that may be evaluated in this article, or

claim that may be made by its manufacturer, is not guaranteed or

endorsed by the publisher.

Frontiers in Pharmacology frontiersin.org14

Yang et al. 10.3389/fphar.2022.989575

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Full-text available

May 2022

Enhancer of zeste homolog 2 (EZH2) is activated in breast cancer, particularly in triple-negative breast cancer (TNBC), and is critical for cell invasion. It interacts with embryonic ectoderm development (EED) in maintaining cancer stem cells (CSC) and epithelial-mesenchymal transition (EMT) properties, hence promoting CSC metastasis. Because the association of EZH2 with EED promotes the catalytic activity of EZH2, inhibiting the EED-EZH2 interaction is a potential therapeutic strategy for treating EZH2-dependent cancer. Although several EED-EZH2 protein-protein interaction (PPI) inhibitors have been developed, few target EED. Here, we identified that a cytisine derivative compound ( 1 ) potently binds EED, thus blocking the EED-EZH2 PPI. Compound 1 was found to inhibit cell proliferation and suppress the growth of 3D tumor spheres of TNBC cells. Moreover, by reversing EMT and decreasing the ratio of CSCs, the compound inhibited TNBC metastasis and invasion ability. Therefore, targeting EED to disrupt the EED-EZH2 PPI may provide a new approach for treating TNBC metastasis. To our knowledge, compound 1 is the first cytisine-based EED-EZH2 PPI inhibitor preventing metastasis in TNBC cells. This study may provide a new avenue for the development of more efficacious EED-EZH2 PPI inhibitors in TNBC treatment.

Palmatine Attenuates Metastatic Lung Colonization of Triple Negative Breast Cancer Cells

Article

Full-text available

Apr 2022

Background: Metastatic breast cancer to the lungs is a serious, life-threatening complication that is difficult to cure. Circulating tumor cells play a key role in the metastatic spread of breast cancer to the lungs via the lymphatic or circulatory system. Palmatine is a protoberberine alkaloid, identified as an active component of traditional African herbal preparations. Palmatine has antimetastatic and antiproliferative effects. The inhibitory activity of palmatine on the metastatic colonization of triple negative breast cancer cells in the lungs was investigated in this study. Methods: 4T1 triple breast cancer cells were transplanted synergically to the thoracic duct of the female balb/c mice via the lymphatic system. Palmatine 1, 5 and 10 mg/kg were administered for 28 days. The lungs were analyzed for levels of arterial blood gas, histological damage, immunohistochemical expression of the metastasis-associated protein 1 (MTA1) and tumor suppressor p53 (p53). Results: Administering palmatine 1–10 mg/kg dose dependently improved hypoxemia, ameliorated metastasis associated lung injury; histology score of 3.33 ± 0.33, 1.67 ± 0.33, 1.33 ± 0.33, decreased lung MTA1 (2.19 ± 0.12, 1.83 ± 0.04, 1.84 ± 0.05) and increased p53 expression (1.99 ± 0.06, 2.27 ± 0.12, 2.34 ± 0.12) respectively. Conclusion: Palmatine preserved lung morphology and demonstrated therapeutic potential in aiding the treatment of lung metastasis.

Reduction of Metastasis via Epigenetic Modulation in a Murine Model of Metastatic Triple Negative Breast Cancer (TNBC)

Article

Full-text available

Mar 2022

Simple Summary We investigate the use of the small molecule epigenetic modulator 4SC-202 as a potential cancer therapeutic or adjuvant for Triple Negative Breast Cancer (TNBC). Epigenetic modulation involves alteration of the cellular phenotype without altering the genotype. Here, we investigate how 4SC-202 affects tumor growth, the ability of tumor cells to migrate, and the growth of tumors in vivo. This study demonstrates that 4SC-202 kills tumor cells, reduces their ability to migrate, and decreases metastasis of the tumor cells and tumor burden in a highly metastatic murine model of TNBC. These preclinical studies provide critical information on the potential efficacy of 4SC-202 as a potential therapeutic or adjuvant for TNBC. Abstract This study investigates the effects of a dual selective Class I histone deacetylase (HDAC)/lysine-specific histone demethylase 1A (LSD1) inhibitor known as 4SC-202 (Domatinostat) on tumor growth and metastasis in a highly metastatic murine model of Triple Negative Breast Cancer (TNBC). 4SC-202 is cytotoxic and cytostatic to the TNBC murine cell line 4T1 and the human TNBC cell line MDA-MB-231; the drug does not kill the normal breast epithelial cell line MCF10A. Furthermore, 4SC-202 reduces cancer cell migration. In vivo studies conducted in the syngeneic 4T1 model, which closely mimics human TNBC in terms of sites of metastasis, reveal reduced tumor burden and lung metastasis. The mechanism of action of 4SC-202 may involve effects on cancer stem cells (CSC) which can self-renew and form metastatic lesions. Approximately 5% of the total 4T1 cell population grown in three-dimensional scaffolds had a distinct CD44high/CD24low CSC profile which decreased after treatment. Bulk transcriptome (RNA) sequencing analyses of 4T1 tumors reveal changes in metastasis-related pathways in 4SC-202-treated tumors, including changes to expression levels of genes implicated in cell migration and cell motility. In summary, 4SC-202 treatment of tumors from a highly metastatic murine model of TNBC reduces metastasis and warrants further preclinical studies.

The Role of LSD1 and LSD2 in Cancers of the Gastrointestinal System: An Update

Article

Full-text available

Mar 2022

Epigenetic mechanisms are known to play a key role in cancer progression. Specifically, histone methylation involves reversible post-translational modification of histones that govern chromatin structure remodelling, genomic imprinting, gene expression, DNA damage repair, and meiotic crossover recombination, among other chromatin-based activities. Demethylases are enzymes that catalyse the demethylation of their substrate using a flavin adenine dinucleotide-dependent amine oxidation process. Lysine-specific demethylase 1 (LSD1) and its homolog, lysine-specific demethylase 2 (LSD2), are overexpressed in a variety of human cancer types and, thus, regulate tumour progression. In this review, we focus on the literature from the last 5 years concerning the role of LSD1 and LSD2 in the main gastrointestinal cancers (i.e., gastric cancer, liver cancer, pancreatic cancer, and colorectal cancer).

LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in gastric cancer

Article

Full-text available

Mar 2022
MOL CANCER

Background Histone lysine-specific demethylase 1 (LSD1) expression has been shown to be significantly elevated in gastric cancer (GC) and may be associated with the proliferation and metastasis of GC. It has been reported that LSD1 repressed tumor immunity through programmed cell death 1 ligand 1 (PD-L1) in melanoma and breast cancer. The role of LSD1 in the immune microenvironment of GC is unknown. Methods Expression LSD1 and PD-L1 in GC patients was analyzed by immunohistochemical (IHC) and Western blotting. Exosomes were isolated from the culture medium of GC cells using an ultracentrifugation method and characterized by transmission electronic microscopy (TEM), nanoparticle tracking analysis (NTA), sucrose gradient centrifugation, and Western blotting. The role of exosomal PD-L1 in T-cell dysfunction was assessed by flow cytometry, T-cell killing and enzyme-linked immunosorbent assay (ELISA). Results Through in vivo exploration, mouse forestomach carcinoma (MFC) cells with LSD1 knockout (KO) showed significantly slow growth in 615 mice than T-cell-deficient BALB/c nude mice. Meanwhile, in GC specimens, expression of LSD1 was negatively correlated with that of CD8 and positively correlated with that of PD-L1. Further study showed that LSD1 inhibited the response of T cells in the microenvironment of GC by inducing the accumulation of PD-L1 in exosomes, while the membrane PD-L1 stayed constant in GC cells. Using exosomes as vehicles, LSD1 also obstructed T-cell response of other cancer cells while LSD1 deletion rescued T-cell function. It was found that while relying on the existence of LSD1 in donor cells, exosomes can regulate MFC cells proliferation with distinct roles depending on exosomal PD-L1-mediated T-cell immunity in vivo. Conclusion LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in GC; this finding indicates a new mechanism with which LSD1 may regulate cancer immunity in GC and provides a new target for immunotherapy against GC.

Berberine alkaloids inhibit the proliferation and metastasis of breast carcinoma cells involving Wnt/β-catenin signaling and EMT

Article

Apr 2022
PHYTOCHEMISTRY

Berberine alkaloids belong to the class of isoquinoline alkaloids that have been shown to possess anticancer potential, berberine exhibits inhibitory effects on breast cancer development. However, the exact mechanisms of action for anti-breast carcinoma of the alkaloids, including epiberberine, berberrubine and dihydroberberine are still unclear. MTT assay, colony formation, wound healing and transwell invasion assays detected these alkaloids suppressed proliferation, migration and invasion of breast cancer cells. Hoechst and Annexin V-FITC/propidium iodide staining were used to analyze the apoptosis of breast cancer cells. Western blotting investigated the changes noted in the expression levels of the key proteins involved in the Wnt signaling pathway and epithelial to mesenchymal transition (EMT). The results showed that inhibited the proliferation of breast cancer cells. Berberine alkaloids inhibited the cell cycle at G2/M phase in MCF-7 cells, but in MDA-MB-231 cells berberine alkaloids arrested the cell cycle in G0/G1 and G2/M phases. By decreasing β-catenin expression, increasing GSK-3β expression and decreasing N-cadherin expression, increasing E-cadherin expression, which proved that epiberberine, berberrubine and dihydroberberine inhibited of metastasis of breast cancer cells through Wnt signaling pathway and reversed EMT except berberine. Furthermore, berberine alkaloids exert their anti-breast cancer effects through the synergistic action of intrinsic and extrinsic pathways of apoptosis. These findings highlight the different effects of different berberine alkaloids on breast cancer cells and confirm that berberine alkaloids may be potentially used in the treatment of breast cancer.

Targeting allosteric regulation of cancer metabolism

Article

May 2022
NAT CHEM BIOL

Metabolic reprogramming is observed across all cancer types. Indeed, the success of many classic chemotherapies stems from their targeting of cancer metabolism. Contemporary research in this area has refined our understanding of tumor-specific metabolic mechanisms and has revealed strategies for exploiting these vulnerabilities selectively. Based on this growing understanding, new small-molecule tools and drugs have been developed to study and target tumor metabolism. Here, we highlight allosteric modulation of metabolic enzymes as an attractive mechanism of action for small molecules that target metabolic enzymes. We then discuss the mechanistic insights garnered from their application in cancer studies and highlight the achievements of this approach in targeting cancer metabolism. Finally, we discuss technological advances in drug discovery for allosteric modulators of enzyme activity.

Novel non-covalent LSD1 inhibitors endowed with anticancer effects in leukemia and solid tumor cellular models

Article

Apr 2022
EUR J MED CHEM

LSD1 is a histone lysine demethylase proposed as therapeutic target in cancer. Chemical modifications applied at C2, C4 and/or C7 positions of the quinazoline core of the previously reported dual LSD1/G9a inhibitor 1 led to a series of non-covalent, highly active, and selective LSD1 inhibitors (2–4 and 6–30) and to the dual LSD1/G9a inhibitor 5 that was more potent than 1 against LSD1. In THP-1 and MV4-11 leukemic cells, the most potent compounds (7, 8, and 29) showed antiproliferative effects at sub-micromolar level without significant toxicity at 1 μM in non-cancer AHH-1 cells. In MV4-11 cells, the new derivatives increased the levels of the LSD1 histone mark H3K4me2 and induced the re-expression of the CD86 gene silenced by LSD1, thereby confirming the inhibition of LSD1 at cellular level. In breast MDA-MB-231 as well as in rhabdomyosarcoma RD and RH30 cells, taken as examples of solid tumors, the same compounds displayed cell growth arrest in the same IC50 range, highlighting a crucial anticancer role for LSD1 inhibition and suggesting no added value for the simultaneous G9a inhibition in these tumor cell lines.

A state-of-the-art review on LSD1 and its inhibitors in breast cancer: Molecular mechanisms and therapeutic significance

Abstract

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