David M Heery

University of Nottingham | Notts · School of Pharmacy

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa....

Mice have been used in biological research for over a century, and their immense contribution to scientific breakthroughs can be seen across all research disciplines, with some of the main beneficiaries being the fields of medicine and life sciences. Genetically engineered mouse models (GEMMs), along with other model organisms, are fundamentally im...

Histone H3 lysine 4 (H3K4) methylation is key epigenetic mark associated with active transcription and is a substrate for the KDM1A/LSD1 and KDM5B/JARID1B lysine demethylases. Increased expression of KDM1A and KDM5B is implicated in many cancer types, including prostate cancer (PCa). Both KDM1A and KDM5B interact with AR and promote androgen regula...

Prostate cancer (PCa) lethality is driven by its progression to a metastatic castration-resistant state, yet the signaling mechanisms underlying metastatic spread remain unknown. Here we show that STAT3 converges with the LKB1/mTORC1 and CREB to control metastatic disease in PCa mouse models. Unexpectedly, STAT3 was found to be upregulated in diabe...

PIP5K1α has emerged as a promising drug target for the treatment of castration-resistant prostate cancer (CRPC), as it acts upstream of the PI3K/AKT signaling pathway to promote prostate cancer (PCa) growth, survival and invasion. However, little is known of the molecular actions of PIP5K1α in this process. Here, we show that siRNA-mediated knockdo...

Low affinity immunoglobulin gamma Fc region receptor III-A (FcγRIIIa) is a cell surface protein that belongs to a family of Fc receptors that facilitate the protective function of the immune system against pathogens. However, the role of FcγRIIIa in prostate cancer (PCa) progression remained unknown. In this study, we found that FcγRIIIa expression...

Invasive lobular carcinoma (ILC) accounts for 10-15% of primary breast cancer and is typically ER+ and non-amplified. There is preclinical evidence that somatic mutation may provide an alternative and tractable mechanism for upregulation of HER2 activity in tumors that do not express HER2 by current clinical criteria. Using large public datasets, w...

Androgen deprivation therapy (ADT) remains a key approach in the treatment of prostate cancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3′‐triiodo‐l‐thyronine (T3) are involved in the progression of PCa. Epidemiologic evidences...

Background: Invasive lobular carcinoma (ILC) accounts for 10-15% of primary breast cancers and is typically estrogen receptor alpha positive (ER+) and ERBB2 non-amplified. Somatic mutations in ERBB2/3 are emerging as a tractable mechanism underlying enhanced human epidermal growth factor 2 (HER2) activity. We tested the hypothesis that therapeutic...

Triple negative or basal-like breast cancer (TNBC) is characterised by aggressive progression, lack of standard therapies and poorer overall survival rates for patients. The bad prognosis, high rate of relapse and resistance against anticancer drugs have been associated with a highly abnormal loss of redox control in TNBC cells. Here, we developed...

Invasive lobular carcinoma accounts for 10-15% of breast cancer cases and typically expresses hormone receptors. Despite this, lobular tumours respond less well to endocrine therapy, and long-term patient outcomes are inferior to those with other breast cancer subtypes. In primary lobular tumours, HER2 is rarely overexpressed due to relative infreq...

BACKGROUND: Invasive lobular carcinoma (ILC) accounts for 10-15% of primary breast cancers and is typically estrogen receptor alpha positive (ER+) and ERBB2 non-amplified. Somatic mutations in ERBB2/3 are emerging as a tractable mechanism underlying enhanced human epidermal growth factor 2 (HER2) activity. We tested the hypothesis that therapeutica...

Androgen deprivation therapy (ADT) remains a key approach in the treatment of prostate cancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3’-triiodo-L-thyronine (T3) are involved in the progression of PCa. Epidemiologic evidence i...

IRF1 (Interferon Regulatory Factor-1) is the prototype of the IRF family of DNA binding transcription factors. IRF1 protein expression is regulated by transient up-regulation in response to external stimuli followed by rapid degradation via the ubiquitin-proteasome system. Here we report that DNA bound IRF1 turnover is promoted by GSK3 (Glycogen Sy...

IRF1 (Interferon Regulatory Factor-1) is the prototype of the IRF family of DNA binding transcription factors. IRF1 protein expression is regulated by transient up-regulation in response to external stimuli followed by rapid degradation via the ubiquitin-proteasome system. Here we report that DNA bound IRF1 turnover is promoted by GSK3β (Glycogen S...

Supplementary material: Supplementary Fig. S1. Cartoon representation of AR LBD homodimer structure showing bound cofactor peptides (LXXLL motifs- orange) and agonist ligand (dihydrotestosterone-DHT- magenta). Sidechains of the Y916 residues are indicated, showing they are distant from the ligand binding pockets and the observed homodimer interface...

Background PAIS exhibits a complex spectrum of phenotypes and pubertal outcomes. The paucity of reliable prognostic indicators can confound management decisions including sex-of-rearing. We assessed whether external masculinisation score (EMS) at birth or functional assays correlates with pubertal outcome in PAIS patients and whether the EMS is hel...

The intestinal lymphatic system plays an important role in the pathophysiology of multiple diseases including lymphomas, cancer metastasis, autoimmune diseases, and human immunodeficiency virus (HIV) infection. It is thus an important compartment for delivery of drugs in order to treat diseases associated with the lymphatic system. Lipophilic prodr...

Introduction Hypoxia (low oxygen) is associated with worst prognosis and therapy resistance in most solid tumours. Hypoxia occurs in ~50% of breast cancer, most frequently in triple negative breast cancer (TNBC), the most aggressive subtype. Hypoxia drives tumour aggressiveness through HIF, which activates genes that promote adaptation to hypoxia,...

Polycomb repressive complex 1 (PRC1) and PRC2 are transcriptional re-pressors that function as key regulators of the self-renewal and differentiation (cell lineage specification) pathways in stem cells. In this issue of Blood, Shima et al¹ report that 2 ubiquitin ligases (Ring1A and Ring1B), which are key components of PRC1 complexes, are essential...

Urogenital schistosomiasis, caused by the parasitic trematode Schistosoma haematobium , affects over 112 million people worldwide. As with S. mansoni infections, the pathology in urogenital schistosomiasis is mainly related to the egg stage, which induces granulomatous inflammation of affected tissues. Schistosoma eggs and their secretions have bee...

Objective: Women with a prior history of polycystic ovary syndrome (PCOS) have an increased risk of endometrial cancer (EC). Aim: To investigate whether the endometrium of women with PCOS possess gene expression changes similar to those found in EC. Design and methods: Patients with EC, PCOS and control women unaffected by either PCOS or EC we...

Background: In addition to cognitive decline, Alzheimer's Disease (AD) is also characterized by agitation and disruptions in activity and sleep. These symptoms typically occur in the evening or night and have been referred to as 'sundowning'. They are especially difficult for carers and there are no specific drug treatments. There is increasing ev...

Photoreceptor-specific nuclear receptor (PNR/NR2E3) and Tailless homolog (TLX/NR2E1) are human orthologs of the NR2E group, a subgroup of phylogenetically related members of the nuclear receptor (NR) superfamily of transcription factors. We assessed the ability of these NRs to form heterodimers with other members of the human NRs representing all m...

The placenta and tumors share important characteristics, including a requirement to establish effective angiogenesis. In the case of the placenta, optimal angiogenesis is required to sustain the blood flow required to maintain a successful pregnancy, whereas in tumors establishing new blood supplies is considered a key step in supporting metastases...

One mechanism of resistance of prostate cancer (PCa) to enzalutamide (MDV3100) treatment is the increased expression of AR variants lacking the ligand binding-domain, the best characterized of which is AR-V7. We have previously reported that Phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), is a lipid kinase that links to CDK1 and AR pathwa...

Infiltrins (or pathogen-secreted host nucleus infiltrating proteins) are potential new targets for the development of more efficient vaccines against helminthic parasites. The archetypal infiltrin is SmIPSE (a.k.a. IPSE/alpha-1), a glycoprotein secreted by Schistosoma mansoni eggs, characterised by the simultaneous presence of a classical secretory...

Bone metastasis is a leading cause of morbidity and mortality in prostate cancer (PCa). While cancer stem-like cells have been implicated as a cell of origin for PCa metastases, the pathways which enable metastatic development at distal sites remain largely unknown. In this study, we illuminate pathways relevant to bone metastasis in this disease....

Schistosoma mansoni and Fasciola hepatica cause schistosomiasis and fascioliasis, respectively, in several parts of the world; while both parasites infect humans, the latter also infects animals. We are interested in elucidating the host parasite relationship at the molecular level, and have identified a potential novel general regulatory mechanism...

Retinoids are natural and synthetic derivatives of vitamin A, also termed retinol. This article will address the current understanding of (i) the uptake, the metabolism, and storage of dietary retinoids; (ii) the molecular mechanisms whereby retinoids activate transcription via the retinoic acid receptor (RAR) and retinoid X receptor (RXR) and ther...

Androgens and the androgen receptor (AR) play crucial roles in male development and the pathogenesis and progression of prostate cancer (PCa). The AR functions as a ligand dependent transcription factor which recruits multiple enzymatically distinct epigenetic coregulators to facilitate transcriptional regulation in response to androgens. Over-expr...

Prostate cancer (PCa) is the most common malignancy affecting men in the western world. While radical prostatectomy and radiation therapy can successfully treat a majority of patients, up to ~30% will experience local recurrence or metastatic disease. Prostate carcinogenesis and progression is typically an androgen dependent process. For this reaso...

Whether the dopamine Drd-2 receptor is necessary for the behavioural action of antipsychotic drugs is an important question, as Drd-2 antagonism is responsible for their debilitating motor side effects. Using Drd-2 null mice (Drd2 -/-) it has previously been shown that Drd-2 is not necessary for antipsychotic drugs to reverse D-amphetamine disrupti...

Histone tail modifications control many nuclear processes by dictating the dynamic exchange of regulatory proteins on chromatin. Here we report novel insights into histone H3 tail structure in complex with the double PHD finger (DPF) of the lysine acetyltransferase MOZ/MYST3/KAT6A. In addition to sampling H3 and H4 modification status, we show that...

Despite their physiological importance, selective interactions between nuclear receptors (NRs) and their cofactors are poorly understood. Here, we describe a novel signature motif (F/YSXXLXXL/Y) in the developmental regulator BCL11A that facilitates its selective interaction with members of the NR2E/F subfamily. Two copies of this motif (named here...

Preferentially expressed antigen in melanoma (PRAME) has been described as a cancer-testis antigen and is associated with leukaemias and solid tumours. Here we show that gene transcription in leukaemic cell lines is rapidly induced by exposure of cells to bacterial PAMPs (pathogen associated molecular patterns) in combination with type 2 interferon...

Drugs that induce psychosis, such as D-amphetamine (AMP), and those that alleviate it, such as antipsychotics, are suggested to exert behavioral effects via dopamine receptor D2 (D2). All antipsychotic drugs are D2 antagonists, but D2 antagonism underlies the severe and debilitating side effects of these drugs; it is therefore important to know whe...

Background Post-translational modifications (PTMs) of histones and other proteins are perturbed in tumours. For example, reduced levels of acetylated H4K16 and trimethylated H4K20 are associated with high tumour grade and poor survival in breast cancer. Drug-like molecules that can reprogram selected histone PTMs in tumour cells are therefore of in...

Preferentially expressed antigen in melanoma (PRAME) has been described as a cancer-testis antigen and is associated with leukaemias and solid tumours. Here we show that PRAME gene transcription in leukaemic cell lines is rapidly induced by exposure of cells to bacterial PAMPs (pathogen associated molecular patterns) in combination with type 2 inte...

Interleukin-4-inducing principle from schistosome eggs (IPSE/alpha-1) is a protein produced exclusively by the eggs of the trematode Schistosoma mansoni. IPSE/alpha-1 is a secretory glycoprotein which activates human basophils via an IgE-dependent but non-antigen-specific mechanism. Sequence analyses revealed a potential nuclear localization signal...

2475 PRAME (preferentially expressed antigen in melanoma) is a germinal tissue-specific gene that is expressed at high levels in a number of haematological malignancies. In AML, PRAME is a positive prognostic indicator, being associated with a favourable response to chemotherapy and increased overall survival, even in the presence of unfavourable k...

PRAME/MAPE/OIP4 is a germinal tissue-specific gene that is also expressed at high levels in haematological malignancies and solid tumours. The physiological functions of PRAME in normal and tumour cells are unknown, although a role in the regulation of retinoic acid signalling has been proposed. Sequence homology and structural predictions suggest...

Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.

The DNA damage response activates several pathways that stall the cell cycle and allow DNA repair. These consist of the well-characterized ATR (Ataxia telangiectasia and Rad-3 related)/CHK1 and ATM (Ataxia telangiectasia mutated)/CHK2 pathways in addition to a newly identified ATM/ATR/p38MAPK/MK2 checkpoint. Crucial to maintaining the integrity of...

The lysine acetyltransferase CREB binding protein (CBP) is required for chromatin modification and transcription at many gene promoters. In fixed cells, a large proportion of CBP colocalises to PML or nuclear bodies. Using live cell imaging, we show here that YFP-tagged CBP expressed in HEK293 cells undergoes gradual accumulation in nuclear bodies,...

Post-translational histone modifications are known to be altered in cancer cells, and loss of selected histone acetylation and methylation marks has recently been shown to predict patient outcome in human carcinoma. Immunohistochemistry was used to detect a series of histone lysine acetylation (H3K9ac, H3K18ac, H4K12ac, and H4K16ac), lysine methyla...

Latent inhibition (LI) is reduced learning to a stimulus that has previously been experienced without consequence. It is an important model of abnormal allocation of salience to irrelevant information in patients with schizophrenia. In rodents LI is abolished by psychotomimetic drugs and in experimental conditions where LI is low in controls, its e...

Lysine acetyltransferases (LATs) are a structurally disparate group of enzymes involved in regulating transcription by participating as cofactors in transcriptional regulatory complexes, and by acetylation of lysine residues in histones and other proteins. Aberrant LAT function probably plays an important part in the pathogenesis of certain cancers...

The promyelocytic leukaemia gene (Pml) is a tumor suppressor identified in acute promyelocytic leukaemia (APL), where it is fused to RAR alpha gene as a result of the chromosomal translocation t(15;17). Pml encodes both nuclear and cytoplasmic isoforms. While nuclear PML has been intensively investigated, cytoplasmic PML proteins are less character...

Nuclear transport proteins such as CSE1, NUP93 and Importin-alpha have recently been shown to be chromatin-associated proteins in yeast, which have unexpected functions in gene regulation. Here we report interactions between the mammalian histone acetyltransferase CBP with nuclear transport proteins CAS (a CSE1 homologue) and Importin-alpha (Impalp...

The promyelocytic leukemia (PML) tumor suppressor of acute promyelocytic leukemia (APL) regulates major apoptotic and growth-suppressive pathways. In APL, PML is involved in a chro-mosomal translocation generating the PML-retinoic acid receptor-(RAR) fusion protein. Two missense mutations in the remaining PML alleles have been identified, which giv...

Glucocorticoids affect the immune system by a number of mechanisms, including modulation of cytokine production in lymphocytes. Glucocorticoids suppress T helper cell type 1 immune responses by decreasing the ability of T cells to respond to interleukin (IL)-12, a major inducer of interferon (IFN)-gamma. IFN-beta increases the expression of the ant...

MOZ-TIF2 and MOZ-CBP are leukemogenic fusion proteins associated with therapy-induced acute myeloid leukemia. These proteins are thought to subvert normal gene expression in differentiating hematopoietic progenitor cells. We have previously shown that MOZ-TIF2 inhibits transcription by CREB-binding protein (CBP)/p300-dependent activators such as nu...

MOZ-TIF2 and MOZ-CBP are leukemogenic fusion proteins associated with therapy-induced acute myeloid leukemia. These proteins are thought to subvert normal gene expression in differentiating hematopoietic progenitor cells. We have previously shown that MOZ-TIF2 inhibits transcription by CREB-binding protein (CBP)/p300-dependent activators such as nu...

The promyelocytic leukemia (PML) tumor suppressor of acute promyelocytic leukemia (APL) regulates major apoptotic and growth-suppressive pathways. In APL, PML is involved in a chromosomal translocation generating the PML-retinoic acid receptor-alpha (RARalpha) fusion protein. Two missense mutations in the remaining PML alleles have been identified,...

Ligand-induced transcription by nuclear receptors involves the recruitment of p160 coactivators such as steroid receptor coactivator 1 (SRC1), in complex with histone acetyltransferases such as CREB-binding protein (CBP) and p300. Here we describe the solution structure of a complex formed by the SRC1 interaction domain (SID) of CBP and the activat...

The regulation of gene expression by estrogen receptor-α (ERα) requires the coordinated and temporal recruitment of diverse sets of transcriptional co-regulator complexes, which mediate nucleosome remodelling and histone modification. Using ERα as bait in a yeast two-hybrid screen, we have identified a novel ERα-interacting protein, ZNF366, which i...

MOZ (monocytic leukaemia zinc finger protein; also known as ZNF220 or MYST3) is a member of the MYST family of protein acetyltransferases. Chromosomal translocations involving the MOZ gene are associated with AML (acute myeloid leukaemia), suggesting that it has a role in haematopoiesis. Recurrent reciprocal translocations fuse the MOZ gene [or the...

Chromosomal rearrangements associated with acute myeloid leukemia (AML) include fusions of the genes encoding the acetyltransferase MOZ or MORF with genes encoding the nuclear receptor coactivator TIF2, p300, or CBP. Here we show that MOZ-TIF2 acts as a dominant inhibitor of the transcriptional activities of CBP-dependent activators such as nuclear...