March 2024
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1 Read
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March 2024
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1 Read
September 2023
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27 Reads
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4 Citations
Background Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related deaths worldwide. Therapeutic options for advanced HCC are limited, which is due to a lack of full understanding of pathogenesis. Cellular senescence is a state of cell cycle arrest, which plays important roles in the pathogenesis of HCC. Mechanisms underlying hepatocellular senescence are not fully understood. LncRNA NEAT1 acts as an oncogene and contributes to the development of HCC. Whether NEAT1 modulates hepatocellular senescence in HCC is unknown. Methods The role of NEAT1 and KIF11 in cellular senescence and tumor growth in HCC was assessed both in vitro and in vivo. RNA pulldown, mass spectrometry, Chromatin immunoprecipitation (ChIP), luciferase reporter assays, RNA FISH and immunofluorescence (IF) staining were used to explore the detailed molecular mechanism of NEAT1 and KIF11 in cellular senescence of HCC. Results We found that NEAT1 was upregulated in tumor tissues and hepatoma cells, which negatively correlated with a senescence biomarker CDKN2A encoding p16INK4a and p14ARF proteins. NEAT1 was reduced in senescent hepatoma cells induced by doxorubicin (DOXO) or serum starvation. Furthermore, NEAT1 deficiency caused senescence in cultured hepatoma cells, and protected against the progression of HCC in a mouse model. During senescence, NEAT1 translocated into cytosol and interacted with a motor protein KIF11, resulting in KIF11 protein degradation and subsequent increased expression of CDKN2A in cultured hepatoma cells. Furthermore, KIF11 knockdown caused senescence in cultured hepatoma cells. Genetic deletion of Kif11 in hepatocytes inhibited the development of HCC in a mouse model. Conclusions Conclusively, NEAT1 overexpression reduces senescence and promotes tumor progression in HCC tissues and hepatoma cells, whereas NEAT1 deficiency causes senescence and inhibits tumor progression in HCC. This is associated with KIF11‐dependent repression of CDKN2A. These findings lay the foundation to develop potential therapies for HCC by inhibiting NEAT1 and KIF11 or inducing senescence.
September 2023
Chinese Science Bulletin (Chinese Version)
September 2023
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41 Reads
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8 Citations
Experimental and Molecular Medicine
The identification of key regulatory factors that control osteoclastogenesis is important. Accumulating evidence indicates that circular RNAs (circRNAs) are discrete functional entities. However, the complexities of circRNA expression as well as the extent of their regulatory functions during osteoclastogenesis have yet to be revealed. Here, based on circular RNA sequencing data, we identified a circular RNA, circFam190a, as a critical regulator of osteoclast differentiation and function. During osteoclastogenesis, circFam190a is significantly upregulated. In vitro, circFam190a enhanced osteoclast formation and function. In vivo, overexpression of circFam190a induced significant bone loss, while knockdown of circFam190a prevented pathological bone loss in an ovariectomized (OVX) mouse osteoporosis model. Mechanistically, our data suggest that circFam90a enhances the binding of AKT1 and HSP90β, promoting AKT1 stability. Altogether, our findings highlight the critical role of circFam190a as a positive regulator of osteoclastogenesis, and targeting circFam190a might be a promising therapeutic strategy for treating pathological bone loss.
August 2023
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40 Reads
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6 Citations
Cell Metabolism
In response to adverse environmental conditions, embryonic development may reversibly cease, a process termed diapause. Recent reports connect this phenomenon with the non-genetic responses of tumors to chemotherapy, but the mechanisms involved are poorly understood. Here, we establish a multifarious role for SMC4 in the switching of colorectal cancer cells to a diapause-like state. SMC4 attenuation promotes the expression of three investment phase glycolysis enzymes increasing lactate production while also suppressing PGAM1. Resultant high lactate levels increase ABC transporter expression via histone lactylation, rendering tumor cells insensitive to chemotherapy. SMC4 acts as co-activator of PGAM1 transcription, and the coordinate loss of SMC4 and PGAM1 affects F-actin assembly, inducing cytokinesis failure and polyploidy, thereby inhibiting cell proliferation. These insights into the mechanisms underlying non-genetic chemotherapy resistance may have significant implications for the field, advancing our understanding of aerobic glycolysis functions in tumor and potentially informing future therapeutic strategies.
April 2023
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45 Reads
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2 Citations
Cell Death Discovery
Sestrins are a small gene family of pleiotropic factors whose actions promote cell adaptation to a range of stress conditions. In this report we disclose the selective role of Sestrin2 (SESN2) in dampening aerobic glycolysis to adapt to limiting glucose conditions. Removal of glucose from hepatocellular carcinoma (HCC) cells inhibits glycolysis associated with the downregulation of the rate-limiting glycolytic enzyme hexokinase 2 (HK2). Moreover, the accompanying upregulation of SESN2 through an NRF2/ATF4-dependent mechanism plays a direct role in HK2 regulation by destabilizing HK2 mRNA. We show SESN2 competes with insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) for binding with the 3′-UTR region of HK2 mRNA. Interactions between IGF2BP3 and HK2 mRNA result in their coalescence into stress granules via liquid-liquid phase separation (LLPS), a process which serves to stabilize HK2 mRNA. Conversely, the enhanced expression and cytoplasmic localization of SESN2 under glucose deprivation conditions favors the downregulation of HK2 levels via decreases in the half-life of HK2 mRNA. The resulting dampening of glucose uptake and glycolytic flux inhibits cell proliferation and protect cells from glucose starvation-induced apoptotic cell death. Collectively, our findings reveal an intrinsic survival mechanism allowing cancer cells to overcome chronic glucose shortages, also providing new mechanistic insights into SESN2 as an RNA-binding protein with a role in reprogramming of cancer cell metabolism.
March 2023
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199 Reads
Given the high prevalence and relapse rates of hepatocellular carcinoma (HCC), an increased capacity for early identification of patients most at risk for post-resection recurrence would help improve patient outcomes and prioritize health care resources. Here, we combined spatial multi-transcriptomics and proteomics approaches to characterize the tumor and immunological landscape of 61 samples. We observed a spatial and HCC-recurrence-associated distribution of natural killer (NK) cells in the invasive front and tumor center. Using artificial-intelligence alongside an extreme gradient-boosting algorithm, we developed the Tumor Immune MicroEnvironment Spatial (“TIMES”) score based on the expression of five NK-associated markers (SPON2, ZFP36L2, ZFP36, VIM, and HLA-DRB1) to predict HCC recurrence. We also demonstrated that TIMES score (HR = 29.6, P < 0.001) outperforms the current standard tools for patient risk stratification including the TNM (HR = 1.93, P = 0.113) and BCLC (HR = 1.55, P = 0.253) systems. In the clinic, we validated the model in 103 patients from three multi-centered cohorts achieve a real-world sensitivity of 90.00% and specificity of 90.24%. In the lab, following up on the individual marker with the highest prediction accuracy, in vivo models revealed that SPON2 increases IFN-γ secretion and enhances infiltration potential of NK cells at the invasive front. Additionally, we established the TIMES score on a publicly accessible website that can be easily achieved by different levels of pathology labs to facilitate global prediction of HCC recurrence risk and stratification of high-risk patients. With its ability to efficiently stratify high-risk patients, it exemplifying the utility of artificial intelligence to improve our understanding on TIME features that underlie tumor progression.
January 2023
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37 Reads
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9 Citations
Cell Reports
Succinate dehydrogenase (SDH) is a heterotetrameric enzyme complex belonging to the mitochondrial respiratory chain and uniquely links the tricarboxylic acid (TCA) cycle with oxidative phosphorylation. Cancer-related SDH mutations promote succinate accumulation, which is regarded as an oncometabolite. Post-translational modifications of SDH complex components are known to regulate SDH activity, although the contribution of SUMOylation remains unclear. Here, we show that SDHA is SUMOylated by PIAS3 and deSUMOylated by SENP2, events dictating the assembly and activity of the SDH complex. Moreover, CBP acetylation of SENP2 negatively regulates its deSUMOylation activity. Under glutamine deprivation, CBP levels decrease, and the ensuing SENP2 activation and SDHA deSUMOylation serve to concurrently dampen the TCA cycle and electron transport chain (ETC) activity. Along with succinate accumulation, this mechanism avoids excessive reactive oxygen species (ROS) production to promote cancer cell survival. This study elucidates a major function of mitochondrial-localized SENP2 and expands our understanding of the role of SUMOylation in resolving metabolic stress.
December 2022
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33 Reads
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14 Citations
Journal of Experimental & Clinical Cancer Research
Background: Altered glycolysis is the most fundamental metabolic change associated with the Warburg effect. Some glycolytic enzymes such as PKM2, the dominant pyruvate kinase in cancer cells, have been shown to engage in non-glycolytic functions that contribute to tumor metabolism. However, the precise mechanisms are not completely understood. Methods: The role of MNX1-AS1 in hepatocellular carcinoma progression was assessed both in vitro and in vivo. Northern blotting, RNA pulldown, mass spectrometry, RNA-binding protein immunoprecipitation, ChIP, luciferase reporter assays, RNA FISH and immunofluorescence staining were used to explore the detail molecular mechanism of MNX1-AS1 in hepatocellular carcinoma (HCC). Results: Here we dissect how MNX1-AS1, a long non-coding RNA (lncRNA), reinforces the Warburg effect through facilitating the non-glycolytic actions of PKM2 in the cell nucleus. We found that MNX1-AS1 expression was frequently overexpressed in HCC-derived cell lines and tissues compared to their normal hepatic cell counterparts, a finding consistent with its status as pan-cancer expressed lncRNA. In the context of HCC, we show MNX1-AS1 acts as a scaffold to promote interactions between PKM2 and importin α5. In response to EGFR activation, the resulting ternary complex drives the translocation of PKM2 into the nucleus. In consequence, glycolytic pathway components including key mediators of the Warburg effect (LDHA, GLUT1 and PDK1) are upregulated though the coactivator function of PKM2. Manipulating MNX1-AS1 elicited robust effects on glycolysis associated with marked changes in HCC growth in vitro and in xenograft models, indicative of the significant contribution of MNX1-AS1 to tumorigenic phenotypes. Moreover, while MNX1-AS1 expression is driven by c-Myc, its actions associated with PKM2 were shown to be downstream and independent of c-Myc. Conclusions: Given the status of MNX1-AS1 as a pan-cancer upregulated lncRNA, this implicitly highlights the potential of targeting MNX1-AS1 to selectively counter the Warburg effect in a range of tumor types.
November 2022
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28 Reads
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9 Citations
Cell Reports
Many metabolism-related genes undergo alternative splicing to generate circular RNAs, but their functions remain poorly understood. Here we report that circPRKAA1, a circular RNA (circRNA) derived from the α1 subunit of AMP-activated protein kinase (AMPK), fulfills a fundamental role in maintaining lipid homeostasis. circPRKAA1 expression facilitates fatty acid synthesis and promotes lipid storage through two coordinated functions. First, circPRKAA1 promotes a tetrameric complex between the Ku80/Ku70 heterodimer and the mature form of sterol regulatory element-binding protein 1 (mSREBP-1) to enhance the stability of mSREBP-1. Second, circPRKAA1 selectively binds to the promoters of the ACC1, ACLY, SCD1, and FASN genes to recruit mSREBP-1, upregulating their transcription and increasing fatty acid synthesis to promote cancer growth. circPRKAA1 biogenesis is negatively regulated by AMPK activity, with lower AMPK activation in hepatocellular carcinoma tissue frequently associated with elevated circPRKAA1 expression. This work identifies circPRKAA1 as an integral element of AMPK-regulated reprogramming of lipid metabolism in cancer cells.
... This difference may be due to the different rodent models used and the potential dual roles of NEAT1 in regulating oxidative stress under specific contexts. Notably, NEAT1 displayed a predominantly nuclear distribution, which is in agreement with previous reports [60,61]. ...
September 2023
... In the course of advancing age and hormonal cessation, the process of healthy bone remodeling gradually becomes disrupted. Osteoclasts, the exclusive cells accountable for bone resorption, demonstrate deviations in both their quantity and functionality, ultimately resulting in the occurrence of bone loss [3]. Therefore, osteoclasts are widely recognized as a significant focus of research for the development of anti-osteoporosis medications. ...
September 2023
Experimental and Molecular Medicine
... Acetylcholine (ACh) is well recognized as a neurotransmitter. It is a ubiquitous signaling molecule produced by a wide range of non-neuronal cell types [29]. The neurotransmitter ACh has been found to accumulate specifically in DTP states via metabonomics and transcriptomics, and EGFR-TKI treatment increases the expression of choline acetyltransferase, the rate-limiting enzyme in ACh biosynthesis mediated by YAP. ...
August 2023
Cell Metabolism
... Given that none of the glutamine-targeting approaches have had the expected clinical impacts, it behooves us to acquire a more in-depth understanding of the molecular mechanisms that enable cancer cells to overcome glutamine starvation. Our research group has been dedicated to identifying the underlying causes of treatment resistance in glutamine deprivation therapy and has published a series of articles on this [12][13][14] . However, there is a lingering question. ...
January 2023
Cell Reports
... For example, ΔNp63 inhibits the transcription of NEAT1 by recruiting HDAC1 to its promoter, regulating epidermal differentiation [34]. In addition, MNX1-AS1 was found to be induced by Myc and to promote aerobic glycolysis in hepatocellular carcinoma [35]. Through bioinformatics analyses and experimental verification, we discovered that HOXD8 is downregulated in CRC and functions as a TF for LINC01852. ...
December 2022
Journal of Experimental & Clinical Cancer Research
... For instance, the long noncoding RNA ZFAS1 interacts with polyadenylate binding protein 2 (PABP2), promoting the stabilization of SREBP-1 mRNA. Consequently, this interaction elevates the expression of SREBP-1 and its downstream target gene FASN, thereby promoting lipid accumulation in colorectal cancer (CRC) [58]. In conclusion, noncoding RNAs are also involved in regulating the expression of FASN (Fig. 2c and Table 1). ...
November 2022
Cell Reports
... The KCTD (Potassium Channel Tetramerization Domain) family consists of 25 proteins that show a significant amount of structural diversity beyond conserved Bric-à-brac, Tramtrack, and Broad complex (BTB) domains, which are responsible for the oligomerization of KCTD proteins. The functions of all these proteins impact a number of cellular processes in health and disease but remain incompletely understood (reviewed in [1][2][3][4][5]), although they serve many roles in regulating the ubiquitination of other proteins (reviewed in [3]). KCTD proteins can be subdivided, based on homology, into several subgroups, including the related KCTD2, 5, and 17 ( Figure 1A). ...
September 2022
Cell Death and Disease
... RCC cells exhibiting UBB overexpression were subjected to treatment with MG132, resulting in significant upregulation of SP1 (Fig. 4D). SP1, an important transcription factor, is involved in the progression of various cancers [29][30][31]. In ccRCC, the expression of SP1 was consistently increased at the mRNA and protein levels ( Supplementary Fig. 5E-G). ...
September 2022
... [10][11][12][13][14][15][16][17][18] First, PAK4 amplification/mutation occurs among cancers and always related to higher grade/stage and shorter survival. Second, PAK4 plays a pivotal role in cancer malignant process by facilitating abnormal phosphorylation of substrates, such as upregulation of specific oncogenic pathways STAT3, ERK/MAPK, and PI3K/AKT et al. [19][20][21] Additionally, concerning the suppression of the immune microenvironment, PAK4 holds significant influence in modulating tumor cell immune evasion. This is achieved through the activation of the Wnt/ β-catenin signaling pathway. ...
July 2022
Stem Cells
... At a direct level, the targeting of autophagy components by the UPS can both positively and negatively regulate autophagy flux. For example, ubiquitination of the autophagy receptor optineurin by the E3 ligase HACE-1 enhances its association with p62 to enhance autophagy 37 , while the E3 ligase TRIM27 directs ULK1 for proteasomal degradation to dampen autophagy 38 . Notably, both exemplary studies reported their findings in the cancer context where ectopic HACE-1 expression enhances autophagy to inhibit the growth of human lung cancer xenografts, while the genetic deletion of TRIM27 is also associated with enhanced autophagy inhibiting tumor initiation in the PyMT murine mammary tumor model but conversely promoting metastasis. ...
June 2022
The EMBO Journal