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Sun J, Gui Y, Yin H, Yan B, Chen Y, Belke D, Hill JA, Zhou S, Zheng XL. Roles of Brd4 in Vascular Smooth Muscle Cells: Implications for Aging and Vascular Dysfunction. Arterioscler Thromb Vasc Biol 2025. [PMID: 40401376 DOI: 10.1161/atvbaha.124.322158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 05/07/2025] [Indexed: 05/23/2025]
Abstract
BACKGROUND Growing evidence suggests that the epigenetic reader Brd4 (bromodomain-containing protein 4) is involved in aging and aging-related diseases. However, the specific mechanisms by which Brd4 influences vascular aging, especially senescence of vascular smooth muscle cells (SMCs), remain unexplored. METHODS Primary cell cultures were established using mouse aortic SMCs and treated with Brd4 inhibitor, ARV-825, or (+)-JQ1. Primary Brd4flox/flox mouse aortic SMCs were transduced with Ad-Cre virus to induce Brd4 knockout (KO). Senescence was assessed through SA-β-gal (senescence-associated β-galactosidase) staining. A mouse model of inducible SMC-specific Brd4 gene KO (SMC-Brd4-KO) was generated with the Cre-LoxP system. The control and SMC-Brd4-KO mice were evaluated for arterial contractility, blood pressure, arterial stiffness, and Ang II (angiotensin II)-induced vascular aging, as well as transcriptome profiling using RNA-sequencing analysis. RESULTS Brd4 inhibition with ARV-825, (+)-JQ1, or Brd4 knockdown through Ad-Cre virus in Brd4flox/flox SMCs led to cellular senescence. Induced SMC-Brd4-KO in adult mice prevented neointima formation. SMC-Brd4-KO mice exhibited increased aortic stiffness and blood pressure with enhanced arterial contractility ex vivo. In addition, Brd4 expression was downregulated in aortic tissues of aged mice and senescent human aortic SMCs. Furthermore, SMC-Brd4-KO mice displayed more prominent histopathologic features of vascular aging in response to Ang II infusion. Aortic tissues from SMC-Brd4-KO mice showed a more robust contractile response to Ang II and phenylephrine, accompanied by multiple genetic changes, including alterations in cytoskeleton genes. Transcriptomes of Brd4 KO aortas displayed gene signatures of dampened autophagy, intriguingly associated with a downregulation of microtubule genes, including Tuba4a (α-tubulin). Experiments in vitro with Brd4 KO SMCs demonstrated the potential role of impaired autophagy and depleted α-tubulin in mediating induction of senescence in SMCs. CONCLUSIONS Brd4 depletion in SMCs induces senescence, prevents neointima formation, and exacerbates vascular aging, highlighting its crucial roles in vascular functions and diseases.
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Affiliation(s)
- Jiaxing Sun
- Department of Biochemistry and Molecular Biology and Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Alberta, Canada. (J.S., Y.G., B.Y., X.-L.Z.)
- Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China (J.S., S.Z.)
| | - Yu Gui
- Department of Biochemistry and Molecular Biology and Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Alberta, Canada. (J.S., Y.G., B.Y., X.-L.Z.)
| | - Hao Yin
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada (H.Y.)
| | - Binjie Yan
- Department of Biochemistry and Molecular Biology and Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Alberta, Canada. (J.S., Y.G., B.Y., X.-L.Z.)
| | - Yongxiang Chen
- Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Alberta, Canada. (Y.C., D.B.)
| | - Darrell Belke
- Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Alberta, Canada. (Y.C., D.B.)
| | - Joseph A Hill
- Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas (J.A.H.)
| | - Shenghua Zhou
- Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China (J.S., S.Z.)
| | - Xi-Long Zheng
- Department of Biochemistry and Molecular Biology and Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Alberta, Canada. (J.S., Y.G., B.Y., X.-L.Z.)
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Liu ZZ, Ji FH, Piao Y. Non-coding RNAs participate in interactions between senescence and gastrointestinal cancers. Front Genet 2025; 15:1461404. [PMID: 39831201 PMCID: PMC11739115 DOI: 10.3389/fgene.2024.1461404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 12/04/2024] [Indexed: 01/22/2025] Open
Abstract
Relationships between cellular senescence and gastrointestinal cancers have gained prominence in recent years. The currently accepted theory suggests that cellular senescence and cancer occurrence exhibit "double-edged sword" effects. Cellular senescence is related to cancer via four "meta-hallmarks" i.e., genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis, along with two "antagonistic hallmarks" i.e., telomere attrition and stem cell exhaustion. These relationships are characterized by both agonistic and antagonistic elements, but the existence of an intricate dynamic balance remains unknown. Non-coding RNAs (ncRNAs) have vital roles in post-transcriptional regulation, but how they participate in agonistic and antagonistic relationships between cellular senescence and gastrointestinal cancers remains to be fully investigated. In this article, we systematically review how ncRNAs (including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circularRNAs (circRNAs)) participate in interactions between cellular senescence and gastrointestinal cancers. Our aim is to elucidate a triangular relationship between "ncRNAs-senescence-gastrointestinal cancers" which considered these three elements as an equal important standing. We are keen to identify prognostic or therapeutic targets for gastrointestinal cancers from, i.e., aging-related ncRNAs, or discover novel strategies to treat and manage in the elderly. We seek to clarify complex relationships where ncRNAs participate in "senescence-gastrointestinal cancers" interactions.
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Affiliation(s)
| | | | - Ying Piao
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang, China
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Shimizu K, Inuzuka H, Tokunaga F. The interplay between cell death and senescence in cancer. Semin Cancer Biol 2025; 108:1-16. [PMID: 39557316 DOI: 10.1016/j.semcancer.2024.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 11/10/2024] [Accepted: 11/12/2024] [Indexed: 11/20/2024]
Abstract
Cellular senescence is a state of permanent proliferative arrest that occurs in response to DNA damage-inducing endogenous and exogenous stresses, and is often accompanied by dynamic molecular changes such as a senescence-associated secretory phenotype (SASP). Accumulating evidence indicates that age-associated increases in the upstream and downstream signals of regulated cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, are closely related to the induction of cellular senescence and its phenotype. Furthermore, elevated levels of pro-inflammatory SASP factors with aging can be both a cause and consequence of several cell death modes, suggesting the reciprocal effects of cellular senescence and cells undergoing regulated cell death. Here, we review the critical molecular pathways of the regulated cell death forms and describe the crosstalk between aging-related signals and cancer. In addition, we discuss how targeting regulated cell death could be harnessed in therapeutic interventions for cancer. ABBREVIATIONS: Abbreviations that are not standard in this field are defined at their first occurrence in the article and are used consistently throughout the article.
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Affiliation(s)
- Kouhei Shimizu
- Department of Medical Biochemistry, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan.
| | - Hiroyuki Inuzuka
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA02215, USA
| | - Fuminori Tokunaga
- Department of Medical Biochemistry, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
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Balamurli G, Liew AQX, Tee WW, Pervaiz S. Interplay between epigenetics, senescence and cellular redox metabolism in cancer and its therapeutic implications. Redox Biol 2024; 78:103441. [PMID: 39612910 PMCID: PMC11629570 DOI: 10.1016/j.redox.2024.103441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 12/01/2024] Open
Abstract
There is accumulating evidence indicating a close crosstalk between key molecular events regulating cell growth and proliferation, which could profoundly impact carcinogenesis and its progression. Here we focus on reviewing observations highlighting the interplay between epigenetic modifications, irreversible cell cycle arrest or senescence, and cellular redox metabolism. Epigenetic alterations, such as DNA methylation and histone modifications, dynamically influence tumour transcriptome, thereby impacting tumour phenotype, survival, growth and spread. Interestingly, the acquisition of senescent phenotype can be triggered by epigenetic changes, acting as a double-edged sword via its ability to suppress tumorigenesis or by facilitating an inflammatory milieu conducive for cancer progression. Concurrently, an aberrant redox metabolism, which is a function of the balance between reactive oxygen species (ROS) generation and intracellular anti-oxidant defences, influences signalling cascades and genomic stability in cancer cells by serving as a critical link between epigenetics and senescence. Recognizing this intricate interconnection offers a nuanced perspective for therapeutic intervention by simultaneously targeting specific epigenetic modifications, modulating senescence dynamics, and restoring redox homeostasis.
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Affiliation(s)
- Geoffrey Balamurli
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, NUS, Singapore; Chromatin Dynamics and Disease Epigenetics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore
| | - Angeline Qiu Xia Liew
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore; Integrative Science and Engineering Programme (ISEP), NUS Graduate School (NUSGS), NUS, Singapore
| | - Wee Wei Tee
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, NUS, Singapore; Chromatin Dynamics and Disease Epigenetics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore
| | - Shazib Pervaiz
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, NUS, Singapore; Integrative Science and Engineering Programme (ISEP), NUS Graduate School (NUSGS), NUS, Singapore; NUS Medicine Healthy Longevity Program, NUS, Singapore; National University Cancer Institute, National University Health System, Singapore.
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Chen X, Yu T, Li S, Fang H. Inhibition of bromodomain regulates cellular senescence in pancreatic adenocarcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2024; 17:360-370. [PMID: 39544715 PMCID: PMC11558316 DOI: 10.62347/bknq9812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 09/23/2024] [Indexed: 11/17/2024]
Abstract
BACKGROUND Bromodomain and extra terminal domain (BET) proteins are important epigenetic regulators that promote the transcription of genes in the chromatin region associated with acetylated histones. Small molecule BET inhibitor JQ1 suppresses the biologic function of BET proteins in a variety of tumors and inhibits their proliferation. METHODS We investigated the effect of JQ1 in the treatment of pancreatic cancer. In addition, we evaluated the expression level of BRD4 protein in pancreatic cancer tissues using the Gene Expression Profiling Interactive Analysis (GEPIA) and the Human protein Altas databases and analyzed the correlation between BRD4 and the clinicopathologic features and immune checkpoints of pancreatic adenocarcinoma using UALACN and TIMER databases. RESULTS JQ1 significantly inhibited the proliferation of pancreatic adenocarcinoma (PAAD) cells and induced cell senescence but had little effect on Senescence-associated secretory phenotype (SASP). Interestingly, JQ1 inhibited the epithelial-mesenchymal transition (EMT) and Wnt signaling pathways. CONCLUSIONS These results provide a theoretical basis for new targets in the treatment of pancreatic cancer.
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Affiliation(s)
- Xiang Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiujiang University Jiujiang 332000, Jiangxi, China
| | - Tao Yu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiujiang University Jiujiang 332000, Jiangxi, China
| | - Shu Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiujiang University Jiujiang 332000, Jiangxi, China
| | - Hongcai Fang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiujiang University Jiujiang 332000, Jiangxi, China
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Sun J, Gui Y, Zhou S, Zheng XL. Unlocking the secrets of aging: Epigenetic reader BRD4 as the target to combatting aging-related diseases. J Adv Res 2024; 63:207-218. [PMID: 37956861 PMCID: PMC11379999 DOI: 10.1016/j.jare.2023.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 11/03/2023] [Accepted: 11/05/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Aging, a complex and profound journey, leads us through a labyrinth of physiological and pathological transformations, rendering us increasingly susceptible to aging-related diseases. Emerging investigations have unveiled the function of bromodomain containing protein 4 (BRD4) in manipulating the aging process and driving the emergence and progression of aging-related diseases. AIM OF REVIEW This review aims to offer a comprehensive outline of BRD4's functions involved in the aging process, and potential mechanisms through which BRD4 governs the initiation and progression of various aging-related diseases. KEY SCIENTIFIC CONCEPTS OF REVIEW BRD4 has a fundamental role in regulating the cell cycle, apoptosis, cellular senescence, the senescence-associated secretory phenotype (SASP), senolysis, autophagy, and mitochondrial function, which are involved in the aging process. Several studies have indicated that BRD4 governs the initiation and progression of various aging-related diseases, including Alzheimer's disease, ischemic cerebrovascular diseases, hypertension, atherosclerosis, heart failure, aging-related pulmonary fibrosis, and intervertebral disc degeneration (IVDD). Thus, the evidence from this review supports that BRD4 could be a promising target for managing various aging-related diseases, while further investigation is warranted to gain a thorough understanding of BRD4's role in these diseases.
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Affiliation(s)
- Jiaxing Sun
- Departments of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, AB, Canada; Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China
| | - Yu Gui
- Departments of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, AB, Canada
| | - Shenghua Zhou
- Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China.
| | - Xi-Long Zheng
- Departments of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, AB, Canada.
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Ahmadpour Youshanlui M, Yari A, Bahojb Mahdavi SZ, Amini M, Baradaran B, Ahangar R, Pourbagherian O, Mokhtarzadeh AA. BRD4 expression and its regulatory interaction with miR-26a-3p, DLG5-AS1, and JMJD1C-AS1 lncRNAs in gastric cancer progression. Discov Oncol 2024; 15:356. [PMID: 39152304 PMCID: PMC11329449 DOI: 10.1007/s12672-024-01230-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 08/12/2024] [Indexed: 08/19/2024] Open
Abstract
Gastric cancer remains a significant health challenge despite advancements in diagnosis and treatment. Early detection is critical to reducing mortality, necessitating the investigation of molecular mechanisms underlying gastric cancer progression. This study focuses on BRD4 expression and its correlation with miR-26a-3p, DLG5-AS1, and JMJD1C-AS1 lncRNAs in gastric cancer. Analysis of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets revealed significant upregulation of BRD4 in gastric cancer tissues compared to normal tissues, correlating negatively with miR-26a-3p and positively with DLG5-AS1 and JMJD1C-AS1 lncRNAs. Quantitative RT-PCR confirmed these findings in 25 gastric cancer tissue samples and 25 normal samples. BRD4's overexpression was associated with reduced survival rates and older patient age. MiR-26a-3p, a known tumor suppressor, showed decreased expression in gastric cancer tissues, with ROC analysis suggesting it, alongside BRD4, as a potential diagnostic biomarker. Additionally, bioinformatics predicted miR-26a-3p's interaction with BRD4 mRNA. Upregulated lncRNAs DLG5-AS1 and JMJD1C-AS1 likely act as competing endogenous RNAs, sponging miR-26a-3p, thus promoting BRD4 dysregulation. These lncRNAs have not been previously studied in gastric cancer. The findings propose a novel BRD4/lncRNA/miRNA regulatory axis in gastric cancer, highlighting the potential of BRD4, DLG5-AS1, and JMJD1C-AS1 as biomarkers for early diagnosis. Further studies with larger sample sizes and in vivo and in vitro experiments are needed to elucidate this regulatory mechanism's role in gastric cancer progression.
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Affiliation(s)
| | - Amirhossein Yari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ramin Ahangar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Omid Pourbagherian
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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8
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Lee H, Nam J, Jang H, Park YS, Son MH, Lee IH, Eyun SI, Yang JH, Jeon J, Yang S. BRD2-specific inhibitor, BBC0403, inhibits the progression of osteoarthritis pathogenesis in osteoarthritis-induced C57BL/6 male mice. Br J Pharmacol 2024; 181:2528-2544. [PMID: 38600628 DOI: 10.1111/bph.16359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 01/10/2024] [Accepted: 02/20/2024] [Indexed: 04/12/2024] Open
Abstract
BACKGROUND AND PURPOSE The discovery of new bromo- and extra-terminal inhibitors presents new drugs to treat osteoarthritis (OA). EXPERIMENTAL APPROACH The new drug, BBC0403, was identified in the DNA-encoded library screening system by searching for compounds that target BRD (bromodomain-containing) proteins. The binding force with BRD proteins was evaluated using time-resolved fluorescence energy transfer (TR-FRET) and binding kinetics assays. Subsequently, in vitro and ex vivo analyses demonstrated the effects of the BRD2 inhibitor, BBC0403, on OA. For animal experiments, medial meniscus destabilization was performed to create a 12-week-old male C57BL/6 mouse model, and intra-articular (i.a.) injections were administered. Histological and immunohistochemical analyses were then performed. The underlying mechanism was confirmed by gene set enrichment analysis (GSEA) using RNA-seq. KEY RESULTS TR-FRET and binding kinetics assays revealed that BBC0403 exhibited higher binding specificity for BRD2 compared to BRD3 and BRD4. The anti-OA effects of BBC0403 were tested at concentrations of 5, 10 and 20 μM (no cell toxicity in the range tested). The expression of catabolic factors, prostaglandin E2 (PGE2) production and extracellular matrix (ECM) degradation was reduced. Additionally, the i.a. injection of BBC0403 prevented OA cartilage degradation in mice. Finally, BBC0403 was demonstrated to suppress NF-κB and MAPK signalling pathways. CONCLUSION AND IMPLICATIONS This study demonstrated that BBC0403 is a novel BRD2-specific inhibitor and a potential i.a.-injectable therapeutic agent to treat OA.
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Affiliation(s)
- Hyemi Lee
- Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea
| | - Jiho Nam
- Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea
| | - Hahyeong Jang
- Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea
| | | | | | | | - Seong-Il Eyun
- Department of Life Science, Chung-Ang University, Seoul, South Korea
| | - Jae-Hyun Yang
- Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute Harvard Medical School (HMS), Boston, Massachusetts, USA
| | - Jimin Jeon
- Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea
| | - Siyoung Yang
- Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea
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9
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Butler T, Davey MG, Kerin MJ. Molecular Morbidity Score-Can MicroRNAs Assess the Burden of Disease? Int J Mol Sci 2024; 25:8042. [PMID: 39125612 PMCID: PMC11312210 DOI: 10.3390/ijms25158042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 08/12/2024] Open
Abstract
Multimorbidity refers to the presence of two or more chronic diseases and is associated with adverse outcomes for patients. Factors such as an ageing population have contributed to a rise in prevalence of multimorbidity globally; however, multimorbidity is often neglected in clinical guidelines. This is largely because patients with multimorbidity are systematically excluded from clinical trials. Accordingly, there is an urgent need to develop novel biomarkers and methods of prognostication for this cohort of patients. The hallmarks of ageing are now thought to potentiate the pathogenesis of multimorbidity. MicroRNAs are small, regulatory, noncoding RNAs which have been implicated in the pathogenesis and prognostication of numerous chronic diseases; there is a substantial body of evidence now implicating microRNA dysregulation with the different hallmarks of ageing in the aetiology of chronic diseases. This article proposes using the hallmarks of ageing as a framework to develop a panel of microRNAs to assess the prognostic burden of multimorbidity. This putative molecular morbidity score would have many potential applications, including assessing the efficacy of clinical interventions, informing clinical decision making and facilitating wider inclusion of patients with multimorbidity in clinical trials.
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Affiliation(s)
- Thomas Butler
- Department of Surgery, Lambe Institute for Translational Research, University of Galway, H91 TK33 Galway, Ireland; (M.G.D.); (M.J.K.)
| | - Matthew G. Davey
- Department of Surgery, Lambe Institute for Translational Research, University of Galway, H91 TK33 Galway, Ireland; (M.G.D.); (M.J.K.)
| | - Michael J. Kerin
- Department of Surgery, Lambe Institute for Translational Research, University of Galway, H91 TK33 Galway, Ireland; (M.G.D.); (M.J.K.)
- Department of Surgery, University Hospital Galway, Newcastle Road, H91 YR71 Galway, Ireland
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10
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Zhu R, Zhang L, Zhang H, Hu Z. BRD4 promotes LPS-induced endothelial cells senescence via activating and cooperating STING-IRF3 pathway. Cell Signal 2024; 118:111127. [PMID: 38447881 DOI: 10.1016/j.cellsig.2024.111127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 02/12/2024] [Accepted: 03/03/2024] [Indexed: 03/08/2024]
Abstract
Endothelial cells (ECs) senescence is closely associated with the initiation and development of multiple age-related cardiovascular diseases. It is necessary to explore the underlying molecular mechanisms of ECs senescence, which is not only the basis to decipher cellular senescence, but also a novel therapeutic target for the endothelial senescence-related diseases. BRD4, a key epigenetic regulator, is universally related to gene expression regulation and has been reported to accelerate cell senescence. Besides, emerging evidence has suggested that the stimulator of interferon genes protein (STING) can regulate inflammatory and senescence-related diseases. However, whether STING pathway activation is regulated by BRD4 in the context of ECs senescence remains largely unclear. Here, we observed that elevated BRD4 and activated STING-IRF3 signaling pathway during ECs senescence and further confirmed that BRD4 could abolish STING activation. We demonstrated that BRD4 could inhibit E3 ubiquitin ligase HRD1-mediated ubiquitination degradation of STING via inhibiting HRD1 transcription. In addition to the direct regulatory effect of BRD4 on STING activation, we have confirmed that BRD4 cooperates with IRF3 and P65 to promote SASP gene expression, thereby accelerating ECs senescence. Here, we proposed a novel mechanism underlying BRD4' key dual role in activating the STING pathway during ECs senescence.
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Affiliation(s)
- Ruigong Zhu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing City 210023, China; State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang City 550014, China.
| | - Lei Zhang
- The Fifth People's Hospital of Huai'an, Huaiyin Hospital of Huai'an, Huai'an City 223300, China.
| | - Hao Zhang
- The Affiliated Tumor Hospital of Nantong University, Nantong Tumor Hospital, Nantong City 226006, China.
| | - Zhifeng Hu
- The Fifth People's Hospital of Huai'an, Huaiyin Hospital of Huai'an, Huai'an City 223300, China.
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11
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Hashimoto M, Masuda T, Nakano Y, Tobo T, Saito H, Koike K, Takahashi J, Abe T, Ando Y, Ozato Y, Hosoda K, Higuchi S, Hisamatsu Y, Toshima T, Yonemura Y, Hata T, Uemura M, Eguchi H, Doki Y, Mori M, Mimori K. Tumor suppressive role of the epigenetic master regulator BRD3 in colorectal cancer. Cancer Sci 2024; 115:1866-1880. [PMID: 38494600 PMCID: PMC11145117 DOI: 10.1111/cas.16129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 02/13/2024] [Accepted: 02/16/2024] [Indexed: 03/19/2024] Open
Abstract
Bromodomain and extraterminal domain (BET) family proteins are epigenetic master regulators of gene expression via recognition of acetylated histones and recruitment of transcription factors and co-activators to chromatin. Hence, BET family proteins have emerged as promising therapeutic targets in cancer. In this study, we examined the functional role of bromodomain containing 3 (BRD3), a BET family protein, in colorectal cancer (CRC). In vitro and vivo analyses using BRD3-knockdown or BRD3-overexpressing CRC cells showed that BRD3 suppressed tumor growth and cell cycle G1/S transition and induced p21 expression. Clinical analysis of CRC datasets from our hospital or The Cancer Genome Atlas revealed that BET family genes, including BRD3, were overexpressed in tumor tissues. In immunohistochemical analyses, BRD3 was observed mainly in the nucleus of CRC cells. According to single-cell RNA sequencing in untreated CRC tissues, BRD3 was highly expressed in malignant epithelial cells, and cell cycle checkpoint-related pathways were enriched in the epithelial cells with high BRD3 expression. Spatial transcriptomic and single-cell RNA sequencing analyses of CRC tissues showed that BRD3 expression was positively associated with high p21 expression. Furthermore, overexpression of BRD3 combined with knockdown of, a driver gene in the BRD family, showed strong inhibition of CRC cells in vitro. In conclusion, we demonstrated a novel tumor suppressive role of BRD3 that inhibits tumor growth by cell cycle inhibition in part via induction of p21 expression. BRD3 activation might be a novel therapeutic approach for CRC.
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Affiliation(s)
- Masahiro Hashimoto
- Department of SurgeryKyushu University Beppu HospitalBeppuJapan
- Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineSuitaJapan
| | - Takaaki Masuda
- Department of SurgeryKyushu University Beppu HospitalBeppuJapan
| | - Yusuke Nakano
- Department of SurgeryKyushu University Beppu HospitalBeppuJapan
- Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineSuitaJapan
| | - Taro Tobo
- Department of PathologyKyushu University Beppu HospitalBeppuJapan
| | - Hideyuki Saito
- Department of SurgeryKyushu University Beppu HospitalBeppuJapan
| | - Kensuke Koike
- Department of SurgeryKyushu University Beppu HospitalBeppuJapan
| | | | - Tadashi Abe
- Department of SurgeryKyushu University Beppu HospitalBeppuJapan
| | - Yuki Ando
- Department of SurgeryKyushu University Beppu HospitalBeppuJapan
| | - Yuki Ozato
- Department of SurgeryKyushu University Beppu HospitalBeppuJapan
- Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineSuitaJapan
| | - Kiyotaka Hosoda
- Department of SurgeryKyushu University Beppu HospitalBeppuJapan
| | - Satoshi Higuchi
- Department of SurgeryKyushu University Beppu HospitalBeppuJapan
- Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineSuitaJapan
| | | | - Takeo Toshima
- Department of SurgeryKyushu University Beppu HospitalBeppuJapan
| | - Yusuke Yonemura
- Department of SurgeryKyushu University Beppu HospitalBeppuJapan
| | - Tsuyoshi Hata
- Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineSuitaJapan
| | - Mamoru Uemura
- Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineSuitaJapan
| | - Hidetoshi Eguchi
- Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineSuitaJapan
| | - Yuichiro Doki
- Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineSuitaJapan
| | - Masaki Mori
- Tokai University School of MedicineIseharaJapan
| | - Koshi Mimori
- Department of SurgeryKyushu University Beppu HospitalBeppuJapan
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12
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Shi A, Lin C, Wang J, Chen Y, Zhong J, Lyu J. EPRIM: An approach of identifying cancer immune-related epigenetic regulators. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102100. [PMID: 38222302 PMCID: PMC10784696 DOI: 10.1016/j.omtn.2023.102100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 12/08/2023] [Indexed: 01/16/2024]
Abstract
Epigenetic regulation contributes to the dysregulation of gene expression involved in cancer biology. Nevertheless, the roles of epigenetic regulators (ERs) in tumor immunity and immune response remain basically unclear. Here, we developed the epigenetic regulator in immunology (EPRIM) approach to identify immune-related ERs and comprehensively dissected the ER regulation in tumor immune response across 33 cancers. The identified immune-related ERs were related to immune infiltration and could stratify cancer patients into two risk groups in multiple independent datasets. These patient groups were characterized by distinct immune functions, immune infiltrates, driver gene mutations, and prognoses. Furthermore, we constructed an immune ER-based signature and highlighted its potential utility in predicting clinical benefit from immunotherapy and selecting therapeutic agents. Taken together, our identification and evaluation of immune-related ERs highlight the usefulness of EPRIM for the understanding of ERs in immune regulation and the clinical relevance in evaluation of cancer patient prognosis and response to immune checkpoint blockade therapy.
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Affiliation(s)
- Aiai Shi
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, People’s Republic of China
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325001, People’s Republic of China
- Institute of Theoretical Physics, Chinese Academy of Sciences, Beijing 100190, People’s Republic of China
| | - Chaohuan Lin
- Postgraduate Training Base Alliance of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, People’s Republic of China
| | - Jilu Wang
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China
| | - Ying’ao Chen
- Postgraduate Training Base Alliance of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, People’s Republic of China
| | - Jinjin Zhong
- Wenzhou Key Laboratory of Biophysics, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325001, China
| | - Jie Lyu
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, People’s Republic of China
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325001, People’s Republic of China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325001, People’s Republic of China
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13
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Yang L, Jing Y, Xia X, Yin X. ARV-825 Showed Antitumor Activity against BRD4-NUT Fusion Protein by Targeting the BRD4. JOURNAL OF ONCOLOGY 2023; 2023:9904143. [PMID: 38130463 PMCID: PMC10735731 DOI: 10.1155/2023/9904143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 10/07/2023] [Accepted: 12/01/2023] [Indexed: 12/23/2023]
Abstract
Objective The bromodomain-containing 4 (BRD4) is a member of the bromodomain and extra terminal domain (BET) family, which is an important epigenetic reader. It is currently a promising oncology target. In some tumors, BET bromodomain inhibitors have demonstrated promising results. Proteolysis-targeting methods (PROTAC), which rapidly and effectively degrade BRD4, have displayed considerable potential in the treatment of tumors in recent years. The purpose of this study is to examine the potential impact of BRD4 PROTAC compounds ARV-825 on oncogene BRD4-NUT fused protein in NUT carcinoma. Methods The effectiveness of ARV-825 was evaluated at the cellular level using the cell counting kit 8 test, wound healing, cell transfection, western blotting analysis, and RNA sequencing. The effectiveness of ARV-825 was also examined in vivo using a xenograft model. Results The BRD4-NUT fusion gene was overexpressed in 3T3 cells, and the pathogenic fusion gene was simulated. The results showed that the overexpression of BRD4-NUT could promote the proliferation and migration of 3T3 cells, but the expression of BRD4 protein was degraded after the addition of the novel cereblon-based PROTAC compound ARV-825 against BRD4, resulting in inhibition of BRD4-NUT 3T3 cell proliferation and migration. Further RNA-seq analysis showed that overexpression of BRD4-NUT was accompanied by increased expression of gene (e.g., Myc, E2F, TRAFs, Wnt, Gadd45g, and Sox6) with significantly enriched pathway (e.g., small cell lung cancer, NF-kappa B signaling pathway, and breast cancer), promoted cell cycle from G 1 phase to S phase, and increased cell proliferation and migration, activated the antiapoptosisi signal, led to abnormal cell growth, and ultimately led to tumorigenesis. The addition of ARV-825 effectively rescued this process and effectively inhibited cell vitality, proliferation, and migration. In vivo studies demonstrated that treatment with ARV-825 greatly suppressed tumor growth without causing harmful side effects and downregulated the BRD4-NUT expression level. Conclusion Through the induction of BRD4 protein degradation, ARV-825 can successfully limit BRD4-NUT 3T3 cell proliferation in vitro and in vivo. These findings suggested that the BRD4 inhibitor ARV-825 would be an effective therapeutic strategy for treating NUT carcinoma that with the genetic feature of BRD4-NUT fusion event.
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Affiliation(s)
- Liu Yang
- Applied Biology Laboratory, College of Pharmaceutical and Biological Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China
| | - Yue Jing
- Applied Biology Laboratory, College of Pharmaceutical and Biological Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China
| | - Xia Xia
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
| | - Xiushan Yin
- Applied Biology Laboratory, College of Pharmaceutical and Biological Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China
- Roc Rock Biotechnology (Shenzhen), Shenzhen 518118, China
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14
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Rao H, Cheng W, Yu J, An X, Deng H, Zhang Z, Wu F, Ji F, Li S. [Preliminary Investigation of the Molecular Mechanism of Empagliflozin Suppressing Gastric Cancer Through Mammalian Target of Rapamycin]. SICHUAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF SICHUAN UNIVERSITY. MEDICAL SCIENCE EDITION 2023; 54:1146-1153. [PMID: 38162062 PMCID: PMC10752783 DOI: 10.12182/20231160204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Indexed: 01/03/2024]
Abstract
Objective To predict the intervention targets of empagliflozin (EMPA), a specific inhibitor of sodium-glucose cotransporter 2 (SGLT2), in gastric adenocarcinoma through comprehensive network pharmacology, and to validate the effects and the molecular mechanisms of EMPA through cellular and molecular biology experiments. Methods Bioinformatics analysis of gastric adenocarcinoma was conducted to assess the correlation between gastric adenocarcinoma prognosis and SGLT2 expression. Network pharmacology was utilized to identify shared targets of EMPA and gastric adenocarcinoma. AGS cells, a human gastric adenocarcinoma cells line, were incubated with EMPA at different concentrations for 24 h and, then, cell proliferation was assessed using the CCK8 assay. After AGS cells were incubated with EMPA at the doses of 0, 3, and 6 mmol/L, real-time cell analysis (RTCA) and 5-ethynyl-2-deoxyuridine (EdU) incorporation were used to evaluate EMPA's inhibitory effects on the proliferation of the AGS cells. In addition, wound healing and Transwell assays were performed to assess the inhibitory effect of EMPA on the migration and invasion of the APC cells and Western blot analysis was conducted to examine the expression of mammalian target of rapamycin (mTOR) and phosphorylated mTOR (p-mTOR). BALB/c (nu/nu) nude mice were implanted with 5×106 AGS cells in the axilla. The mice were divided into three groups, a control group, a low-dose group, and a high-dose group, each consisting of 7 mice. After one week, the control group received daily intraperitoneal injections of normal saline, while the low-dose group and high-dose group received daily intraperitoneal injections of EMPA at the doses of 3 mg/kg and 5 mg/kg, respectively. The tumor volume was measured one week after the drug intervention started. Results Gastric adenocarcinoma patients with low expression of SGLT2 exhibited longer survival time and higher survival rate than those with high expression of SGLT2 did. A total of 104 EMPA-related potential targets and 2028 targets associated with gastric adenocarcinoma were identified. Among these, 45 targets associated with gastric adenocarcinoma overlapped with potential targets of EMPA. Further analysis revealed 10 relevant pathways and 4 core genes. The core genes were cyclin-dependent kinase 4 (CDK4), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), mTOR, and cyclin E1 (CCNE1). CCK-8 assay revealed that EMPA at concentrations ranging from 0.39 to 50 mmol/L effectively inhibited the proliferation of AGS cells. RTCA results indicated a downward shift in the cell growth curve. In comparison to the findings for the control group, EdU assay demonstrated that EMPA at the concentrations of 3 mmol/L and 6 mmol/L significantly inhibited AGS cell proliferation (P<0.05). Results from wound healing and Transwell assays indicated a decrease in the levels of cell migration and invasion (P<0.05) and, notably, there was a significant difference between the high and low-dose EMPA groups (P<0.05). Western blot showed no statistically significant difference in the expression of total mTOR protein between the groups. However, the expression of p-mTOR in the 3 mmol/L and 6 mmol/L EMPA groups decreased compared to that of the control group (P<0.05), with the 6 mmol/L EMPA group exhibiting a more pronounced reduction (P<0.05). Nude mice xenograft tumor experiment demonstrated that, compared to that of the control group, the tumor volumes in the EMPA-treatment groups were significantly reduced (P<0.05), with the high-dose group showing a more pronounced reduction (P<0.05). Conclusion EMPA inhibits the abnormal proliferation and migration of gastric adenocarcinoma cells, potentially through the modulation of mTOR protein activation. This study provides new potential medication and intervention targets for gastric adenocarcinoma treatment.
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Affiliation(s)
- Huiling Rao
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
- （ 400038） Department of Medical Engineering, The First Affiliated Hospital of Army Medical University, Chongqing 400038, China
| | - Wang Cheng
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Juan Yu
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Xiaotong An
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Haojun Deng
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Zhaoyang Zhang
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Fuyun Wu
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Fuyun Ji
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Shan Li
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
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15
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Talukdar PD, Chatterji U. Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases. Signal Transduct Target Ther 2023; 8:427. [PMID: 37953273 PMCID: PMC10641101 DOI: 10.1038/s41392-023-01651-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 08/27/2023] [Accepted: 09/10/2023] [Indexed: 11/14/2023] Open
Abstract
Specific cell states in metazoans are established by the symphony of gene expression programs that necessitate intricate synergic interactions between transcription factors and the co-activators. Deregulation of these regulatory molecules is associated with cell state transitions, which in turn is accountable for diverse maladies, including developmental disorders, metabolic disorders, and most significantly, cancer. A decade back most transcription factors, the key enablers of disease development, were historically viewed as 'undruggable'; however, in the intervening years, a wealth of literature validated that they can be targeted indirectly through transcriptional co-activators, their confederates in various physiological and molecular processes. These co-activators, along with transcription factors, have the ability to initiate and modulate transcription of diverse genes necessary for normal physiological functions, whereby, deregulation of such interactions may foster tissue-specific disease phenotype. Hence, it is essential to analyze how these co-activators modulate specific multilateral processes in coordination with other factors. The proposed review attempts to elaborate an in-depth account of the transcription co-activators, their involvement in transcription regulation, and context-specific contributions to pathophysiological conditions. This review also addresses an issue that has not been dealt with in a comprehensive manner and hopes to direct attention towards future research that will encompass patient-friendly therapeutic strategies, where drugs targeting co-activators will have enhanced benefits and reduced side effects. Additional insights into currently available therapeutic interventions and the associated constraints will eventually reveal multitudes of advanced therapeutic targets aiming for disease amelioration and good patient prognosis.
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Affiliation(s)
- Priyanka Dey Talukdar
- Cancer Research Laboratory, Department of Zoology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, 700019, West Bengal, India
| | - Urmi Chatterji
- Cancer Research Laboratory, Department of Zoology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, 700019, West Bengal, India.
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16
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Yuan M, Yang B, Rothschild G, Mann JJ, Sanford LD, Tang X, Huang C, Wang C, Zhang W. Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential. Signal Transduct Target Ther 2023; 8:309. [PMID: 37644009 PMCID: PMC10465587 DOI: 10.1038/s41392-023-01519-z] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 05/14/2023] [Accepted: 05/31/2023] [Indexed: 08/31/2023] Open
Abstract
Major depressive disorder (MDD) is a chronic, generally episodic and debilitating disease that affects an estimated 300 million people worldwide, but its pathogenesis is poorly understood. The heritability estimate of MDD is 30-40%, suggesting that genetics alone do not account for most of the risk of major depression. Another factor known to associate with MDD involves environmental stressors such as childhood adversity and recent life stress. Recent studies have emerged to show that the biological impact of environmental factors in MDD and other stress-related disorders is mediated by a variety of epigenetic modifications. These epigenetic modification alterations contribute to abnormal neuroendocrine responses, neuroplasticity impairment, neurotransmission and neuroglia dysfunction, which are involved in the pathophysiology of MDD. Furthermore, epigenetic marks have been associated with the diagnosis and treatment of MDD. The evaluation of epigenetic modifications holds promise for further understanding of the heterogeneous etiology and complex phenotypes of MDD, and may identify new therapeutic targets. Here, we review preclinical and clinical epigenetic findings, including DNA methylation, histone modification, noncoding RNA, RNA modification, and chromatin remodeling factor in MDD. In addition, we elaborate on the contribution of these epigenetic mechanisms to the pathological trait variability in depression and discuss how such mechanisms can be exploited for therapeutic purposes.
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Affiliation(s)
- Minlan Yuan
- Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Biao Yang
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Gerson Rothschild
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
| | - J John Mann
- Department of Psychiatry, Columbia University, New York, NY, 10032, USA
- Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, 10032, USA
- Department of Radiology, Columbia University, New York, NY, 10032, USA
| | - Larry D Sanford
- Sleep Research Laboratory, Center for Integrative Neuroscience and Inflammatory Diseases, Pathology and Anatomy, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Xiangdong Tang
- Sleep Medicine Center, Department of Respiratory and Critical Care Medicine, Mental Health Center, Translational Neuroscience Center, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Canhua Huang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chuang Wang
- Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in School of Medicine, Ningbo University, Ningbo, Zhejiang, 315211, China.
| | - Wei Zhang
- Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Medical Big Data Center, Sichuan University, Chengdu, 610041, China.
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17
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Chen Q, Peng Q, Cai J, Liu Y, Lu X, Xiong W, Zeng Z, Li G, Li X, Li X, Xiang B, Yi M, Chen P. Super Enhancer Driven Hyaluronan Synthase 3 Promotes Malignant Progression of Nasopharyngeal Carcinoma. J Cancer 2023; 14:1751-1762. [PMID: 37476195 PMCID: PMC10355197 DOI: 10.7150/jca.83954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 05/23/2023] [Indexed: 07/22/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant tumor of the head and neck with high metastatic and invasive nature. Super enhancers (SEs) control the expression of cell identity genes and oncogenes during tumorigenesis. As a glycosaminoglycan in the tumor microenvironment, hyaluronan (HA) is associated with cancer development. High expression of hyaluronan synthase 3 (HAS3) resulted in HA deposition, which promoted the growth of cancer cell. However, its role in NPC development remains elusive. We demonstrated that the levels of HAS3 mRNA or protein were increased in NPC cell lines. Transcription of HAS3 is associated with SE. Disruption of SE by bromodomain containing 4 (BRD4) inhibitor JQ1 resulted in downregulation of HAS3 and inhibition of cell proliferation and invasiveness in NPC cells. Inhibition of HA synthesis by HAS inhibitor 4-MU suppressed cell growth and invasion of NPC cells, whereas HA treatment exerted opposite effects. Genetically silencing HAS3 in HK1 and FaDu NPC cells attenuated cell proliferation and mobility, while re-expression of HAS3 enhanced malignant potential of CNE1 and CNE2 NPC cells. Furthermore, loss of HAS3 impaired metastatic potential of HK1 cells in nude mice. Mechanistically, inhibition of HA synthesis by chemical inhibitor or silencing HAS3 led to reduction of the levels of phosphorylation of EGFR, AKT, and ERK proteins. In contrast, exogenous HA treatment or forced expression of HAS3 activated EGFR/AKT/ERK signaling cascade. This study suggested that HAS3 is driven by SE and overexpressed in NPC. High expression of HAS3 promotes the malignant features of NPC via activation of EGFR/AKT/ERK signaling pathway.
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Affiliation(s)
- Quanzhu Chen
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008 Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078 Hunan, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha 410013 Hunan, China
| | - Qian Peng
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008 Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078 Hunan, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha 410013 Hunan, China
| | - Jing Cai
- Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha 410000 Hunan, China
| | - Ying Liu
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008 Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078 Hunan, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha 410013 Hunan, China
| | - Xingxing Lu
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008 Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078 Hunan, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha 410013 Hunan, China
| | - Wei Xiong
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008 Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078 Hunan, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha 410013 Hunan, China
| | - Zhaoyang Zeng
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008 Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078 Hunan, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha 410013 Hunan, China
| | - Guiyuan Li
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008 Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078 Hunan, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha 410013 Hunan, China
| | - Xiaoling Li
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008 Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078 Hunan, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha 410013 Hunan, China
| | - Xiayu Li
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha 410013 Hunan, China
| | - Bo Xiang
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008 Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078 Hunan, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha 410013 Hunan, China
| | - Mei Yi
- Department of Dermatology; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008 Hunan, China
| | - Pan Chen
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 Hunan, China
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18
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Ma L, Wang J, Zhang Y, Fang F, Ling J, Chu X, Zhang Z, Tao Y, Li X, Tian Y, Li Z, Sang X, Zhang K, Lu L, Wan X, Chen Y, Yu J, Zhuo R, Wu S, Lu J, Pan J, Hu S. BRD4 PROTAC degrader MZ1 exerts anticancer effects in acute myeloid leukemia by targeting c-Myc and ANP32B genes. Cancer Biol Ther 2022; 23:1-15. [PMID: 36170346 PMCID: PMC9543111 DOI: 10.1080/15384047.2022.2125748] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 08/17/2022] [Accepted: 09/06/2022] [Indexed: 02/08/2023] Open
Abstract
Acute myeloid leukemia (AML) is a highly cancerous and aggressive hematologic disease with elevated levels of drug resistance and relapse resulting in high mortality. Recently, bromodomains and extra-terminal (BET) protein inhibitors have been extensively researched in hematological tumors as potential anticancer agents. MZ1 is a novel BET inhibitor that mediates selective proteins degradation and suppression of tumor growth through proteolysis-targeting chimeras (PROTAC) technology. Accordingly, this study aimed to investigate the role and therapeutic potential of MZ1 in AML. In this study, we first identified that AML patients with high BRD4 expression had poor overall survival than those with low expression group. MZ1 inhibited AML cell growth and induced apoptosis and cycle arrest in vitro. MZ1 induced degradation of BRD4, BRD3 and BRD2 in AML cell strains. Additionally, MZ1 also initiated the cleavage of poly-ADP-ribose polymerase (PARP), which showed cytotoxic effects on NB4 (PML-RARa), K562 (BCR-ABL), Kasumi-1 (AML1-ETO), and MV4-11 (MLL-AF4) cell lines representing different molecular subtypes of AML. In AML mouse leukemia model, MZ1 significantly decreased leukemia cell growth and increased the mouse survival time. According to the RNA-sequencing analysis, MZ1 led to c-Myc and ANP32B genes significant downregulation in AML cell lines. Knockdown of ANP32B promoted AML cell apoptosis and inhibited cell growth. Overall, our data indicated that MZ1 had broad anti-cancer effects on AML cell lines with different molecular lesions, which might be exploited as a novel therapeutic strategy for AML patients.
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Affiliation(s)
- Li Ma
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China
- Department of Pediatrics, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huaian, China
| | - Jianwei Wang
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
| | - Yongping Zhang
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China
| | - Fang Fang
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
| | - Jing Ling
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China
| | - Xinran Chu
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China
| | - Zimu Zhang
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
| | - Yanfang Tao
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
| | - Xiaolu Li
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
| | - Yuanyuan Tian
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
| | - Zhiheng Li
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China
| | - Xu Sang
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China
| | - Kunlong Zhang
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China
| | - Lihui Lu
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China
| | - Xiaomei Wan
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China
| | - Yanling Chen
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China
| | - Juanjuan Yu
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China
| | - Ran Zhuo
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China
| | - Shuiyan Wu
- Intensive Care Unit, Children’s Hospital of Soochow University, Suzhou, China
| | - Jun Lu
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China
| | - Jian Pan
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
| | - Shaoyan Hu
- Department of Hematology, Children’s Hospital of Soochow University, Suzhou, China
- CONTACT Shaoyan HuChildren’s Hospital of Soochow University, Suzhou, 215003, China
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19
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Hu J, Pan D, Li G, Chen K, Hu X. Regulation of programmed cell death by Brd4. Cell Death Dis 2022; 13:1059. [PMID: 36539410 PMCID: PMC9767942 DOI: 10.1038/s41419-022-05505-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 12/04/2022] [Accepted: 12/07/2022] [Indexed: 12/24/2022]
Abstract
Epigenetic factor Brd4 has emerged as a key regulator of cancer cell proliferation. Targeted inhibition of Brd4 suppresses growth and induces apoptosis of various cancer cells. In addition to apoptosis, Brd4 has also been shown to regulate several other forms of programmed cell death (PCD), including autophagy, necroptosis, pyroptosis, and ferroptosis, with different biological outcomes. PCD plays key roles in development and tissue homeostasis by eliminating unnecessary or detrimental cells. Dysregulation of PCD is associated with various human diseases, including cancer, neurodegenerative and infectious diseases. In this review, we discussed some recent findings on how Brd4 actively regulates different forms of PCD and the therapeutic potentials of targeting Brd4 in PCD-related human diseases. A better understanding of PCD regulation would provide not only new insights into pathophysiological functions of PCD but also provide new avenues for therapy by targeting Brd4-regulated PCD.
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Affiliation(s)
- Jinfeng Hu
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
| | - Dun Pan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
| | - Guo Li
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
| | - Kunqi Chen
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
| | - Xiangming Hu
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China.
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20
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Ghafouri-Fard S, Khoshbakht T, Hussen BM, Baniahmad A, Branicki W, Taheri M, Eghbali A. Emerging Role of Non-Coding RNAs in Senescence. Front Cell Dev Biol 2022; 10:869011. [PMID: 35865636 PMCID: PMC9294638 DOI: 10.3389/fcell.2022.869011] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 06/13/2022] [Indexed: 11/13/2022] Open
Abstract
Senescence is defined as a gradual weakening of functional features of a living organism. Cellular senescence is a process that is principally aimed to remove undesirable cells by prompting tissue remodeling. This process is also regarded as a defense mechanism induced by cellular damage. In the course of oncogenesis, senescence can limit tumor progression. However, senescence participates in the pathoetiology of several disorders such as fibrotic disorders, vascular disorders, diabetes, renal disorders and sarcopenia. Recent studies have revealed contribution of different classes of non-coding RNAs in the cellular senescence. Long non-coding RNAs, microRNAs and circular RNAs are three classes of these transcripts whose contributions in this process have been more investigated. In the current review, we summarize the available literature on the impact of these transcripts in the cellular senescence.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tayyebeh Khoshbakht
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
- Center of Research and Strategic Studies, Lebanese French University, Erbil, Iraq
| | - Aria Baniahmad
- Institute of Human Genetics, Jena University Hospitals, Jena, Germany
- *Correspondence: Aria Baniahmad, ; Mohammad Taheri, ; Ahmad Eghbali,
| | - Wojciech Branicki
- Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospitals, Jena, Germany
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- *Correspondence: Aria Baniahmad, ; Mohammad Taheri, ; Ahmad Eghbali,
| | - Ahmad Eghbali
- Anesthesiology Research Center, Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- *Correspondence: Aria Baniahmad, ; Mohammad Taheri, ; Ahmad Eghbali,
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21
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miR-106b as an emerging therapeutic target in cancer. Genes Dis 2022; 9:889-899. [PMID: 35685464 PMCID: PMC9170583 DOI: 10.1016/j.gendis.2021.02.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 01/24/2021] [Accepted: 02/03/2021] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) comprise short non-coding RNAs that function in regulating the expression of tumor suppressors or oncogenes and modulate oncogenic signaling pathways in cancer. miRNAs expression alters significantly in several tumor tissues and cancer cell lines. For example, miR-106b functions as an oncogene and increases in multiple cancers. The miR-106b directly targets genes involved in tumorigenesis, proliferation, invasion, migration, and metastases. This review has focused on the miR-106b function and its downstream target in different cancers and provide perspective into how miR-106 regulates cancer cell proliferation, migration, invasion, and metastases by regulating the tumor suppressor genes. Since miRNAs-based therapies are currently being developed to enhance cancer therapy outcomes, miR-106b could be an attractive and prospective candidate in different cancer types for detection, diagnosis, and prognosis assessment in the tumor.
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22
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Wang Y, Wu Y, Jiang J, Zhang Y, Fu Y, Zheng M, Tao X, Yi J, Mu D, Cao X. The prognostic significance of bromodomain protein 4 expression in solid tumor patients: A meta-analysis. Pathol Res Pract 2022; 234:153918. [PMID: 35561521 DOI: 10.1016/j.prp.2022.153918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 04/15/2022] [Accepted: 04/24/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Cancer is a leading cause of death worldwide. At present, several inhibitors of bromodomain protein 4 have shown promising anti-tumor responses in clinical trials. Numerous studies have reported the value of bromodomain protein 4 expression in predicting the prognosis of patients with cancers, but their conclusions remain controversial. Therefore, we conducted a meta-analysis to explore the association between bromodomain protein 4 and patient prognosis with the aim to provide new directions for the development of strategies for targeted cancer therapy. METHODS The meta-analysis was registered in the International Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/prospero/; Registration No. CRD42020184948) and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. PubMed Central, PubMed, Cochrane Library and Embase were thoroughly searched to identify eligible studies published through March 31, 2021. Odds ratios with 95% confidence intervals were calculated to demonstrate the relationship between bromodomain protein 4 expression and clinicopathological features. We computed pooled estimated hazard ratios with 95% confidence intervals using Stata 12.0 software to clarify the relationship between bromodomain protein 4 expression and overall survival of various cancers. A quality assessment of the eligible articles was performed based on the Newcastle-Ottawa scale. RESULTS A total of 974 patients from 10 studies were enrolled in the meta-analysis. Our results revealed that compared to low bromodomain protein 4 expression, high bromodomain protein 4 expression in cancer tissues was significantly associated with lymph node metastasis (Odds ratio = 3.59, 95% confidence interval: 2.62-4.91), distant metastasis (Odds ratio = 4.22, 95% confidence interval: 2.40-7.45), advanced TNM stage (III+IV vs. I+II: Odds ratio = 3.23, 95% confidence interval: 1.29-8.08), and poorly differentiated tumors (Odds ratio = 1.87, 95% confidence interval: 1.33-2.63). In addition, an elevated expression of bromodomain protein 4 tended to shorten survival time (Hazard ratio = 2.23, 95% confidence interval: 1.62-3.07). The subgroup analysis results showed that bromodomain protein 4 upregulation was related to poor prognosis in patients with digestive system cancers (Hazard ratio = 2.54, 95% confidence interval: 1.85-3.50). CONCLUSION This meta-analysis indicated that bromodomain protein 4 may serve as a promising prognostic biomarker for cancers and a direct effective cancer treatment target.
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Affiliation(s)
- Yueqi Wang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China.
| | - Yanhua Wu
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China.
| | - Jing Jiang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China.
| | - Yangyu Zhang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China.
| | - Yingli Fu
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China.
| | - Min Zheng
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China.
| | - Xuerong Tao
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China.
| | - Jiaxin Yi
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China.
| | - Dongmei Mu
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China.
| | - Xueyuan Cao
- Department of Gastrointestinal Surgery, First Hospital of Jilin University, Changchun, Jilin Province, China.
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Hyperglycemia induces gastric carcinoma proliferation and migration via the Pin1/BRD4 pathway. Cell Death Dis 2022; 8:224. [PMID: 35461311 PMCID: PMC9035156 DOI: 10.1038/s41420-022-01030-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 11/18/2022]
Abstract
Diabetes is a potential risk factor for gastric cancer (GC). Pin1, a peptidyl–prolyl cis/trans isomerase, promotes GC cell proliferation and migration. The role and underlying mechanism of the Pin1/BRD4 axis in hyperglycemia-induced proliferation and migration of GC cells were analyzed in vivo and in vitro. Proliferation and migration of GC cells were measured; Pin1 and BRD4 expression of the cell cycle were determined. Pin1 and BRD4 were downregulated by transfecting Pin1 shRNA lentivirus into GC cells and JQ1-intervention GC cells. Tumor formation and lung metastasis were assessed in vivo. Inhibition of Pin1 and BRD4 significantly suppressed high-glucose (HG)-induced GC cell proliferation and migration. HG enhanced G1/S cell-cycle transition, associated with increased Pin1 and BRD4 expression. Silencing Pin1 significantly downregulated the expression of BRD4 and NAP1L1 and upregulated that of P21 in GC cells. In vivo studies indicated that hyperglycemia promotes tumor growth and lung metastasis by inducing Pin1 and BRD4 expression. Thus, Pin1/BRD4 plays an important role in hyperglycemia-promoted tumor growth. The significance of these findings toward improved prognosis of diabetic patients with GC cannot be underestimated.
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24
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Li H, Luo K, Yang Z, Chen M, Yang X, Wang J, Ying Y, Wu D, Wang Q. Berbamine Suppresses the Growth of Gastric Cancer Cells by Inactivating the BRD4/c-MYC Signaling Pathway. Drug Des Devel Ther 2022; 16:129-141. [PMID: 35046638 PMCID: PMC8762520 DOI: 10.2147/dddt.s338881] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 12/21/2021] [Indexed: 12/14/2022] Open
Abstract
PURPOSE Berbamine (Ber), a bioactive constituent extracted from a traditional Chinese medicinal herb, has been shown to exhibit broad inhibitory activity on a panel of cancer cell types. However, its effects and the underlying molecular mechanisms on gastric cancer (GC) remain poorly understood. METHODS The anti-growth activity of Ber on two GC cell lines and normal gastric epithelial cell line were evaluated using MTS and clone formation assay. Flow cytometry analysis was employed to evaluate the cell cycle distribution and apoptosis of GC cells. Western blot and quantitative PCR (qPCR) analysis were employed to investigate the anti-GC mechanism of Ber. The inhibitory activity and binding affinity of Ber against BRD4 were evaluated by homogeneous time-resolved fluorescence (HTRF) and surface plasmon resonance (SPR) assay, respectively. Molecular docking and molecular simulations were conducted to predict the interaction mode between BRD4 and Ber. RESULTS The results demonstrated that Ber reduced the proliferation of GC cell lines SGC-7901 and BGC-823 and induced cell cycle arrest and apoptosis. Mechanistically, Ber was identified as a novel natural-derived BRD4 inhibitor through multiple experimental assay, and its anti-GC activity was probably mediated by BRD4 inhibition. Molecular modeling studies suggested that Ber might bind to BRD4 primarily through hydrophobic interactions. CONCLUSION Our study uncovered the underlying anti-GC activity of Ber in vitro and suggested that Ber holds promise as a potential lead compound in the discovery of novel BRD4 inhibitors.
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Affiliation(s)
- Hongchun Li
- Department of Cadre Health, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, People's Republic of China
| | - Kexue Luo
- Department of Cadre Health, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, People's Republic of China
| | - Zhuying Yang
- Department of Gastroenterology, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, People's Republic of China
| | - Miao Chen
- Department of Oncology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, 310012, People's Republic of China
| | - Xiuyun Yang
- Department of Cadre Health, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, People's Republic of China
| | - Jiesheng Wang
- Department of Cadre Health, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, People's Republic of China
| | - Yin Ying
- Department of Pharmacy, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, 310012, People's Republic of China
| | - Dengxuan Wu
- Department of Rehabilitation Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, People's Republic of China
| | - Qinxian Wang
- Department of Cadre Health, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, People's Republic of China
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Yang F, Sun Z, Wang D, Du T. MiR-106b-5p regulates esophageal squamous cell carcinoma progression by binding to HPGD. BMC Cancer 2022; 22:308. [PMID: 35317779 PMCID: PMC8941792 DOI: 10.1186/s12885-022-09404-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 03/02/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Several studies have documented the key role of microRNAs (miRNAs) in esophageal squamous cell carcinoma (ESCC). Although the expression of the 15-hydroxyprostaglandin dehydrogenase (HPGD) gene and miR-106b-5p are reportedly linked to cancer progression, their underlying mechanisms in ESCC remain unclear. METHODS mRNA and miRNA expression in ESCC tissues and cells were analyzed using RT-qPCR. Luciferase and RNA pull-down assays were used to identify the interaction between miR-106b-5p and HPGD. Xenograft and pulmonary metastasis models were used to assess tumor growth and metastasis. CCK-8, BrdU, colony formation, adhesion, cell wound healing, Transwell, and caspase-3/7 activity assays, and flow cytometry and western blot analyses were used to examine the function of miR-106-5p and HPGD in ESCC cell lines. RESULTS The findings revealed that miR-106b-5p expression was upregulated in ESCC tissues and cell lines. miR-106b-5p augmented cellular proliferation, colony formation, adhesion, migration, invasion, and proportion of cells in the S-phase, but reduced apoptosis and the proportion of cells in G1-phase. Silencing of miR-106-5p inhibited tumor growth in vivo and pulmonary metastasis. Although HPGD overexpression suppressed proliferation, colony formation, adhesion, migration, and invasion of ESCC cells, it promoted apoptosis and caused cell cycle arrest of the ESCC cells. The results also indicated a direct interaction of HPGD with miR-106b-5p in ESCC cells. Furthermore, miR-106b-5p inhibited HPGD expression, thereby suppressing ESCC tumorigenesis. CONCLUSION Our data suggest that miR-106b-5p enhances proliferation, colony formation, adhesion, migration, and invasion, and induces the cycle progression, but represses apoptosis of ESCC cells by targeting HPGD. This suggests that the miR-106b-5p/HPGD axis may serve as a promising target for the diagnosis and treatment of ESCC.
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Affiliation(s)
- Fan Yang
- Department of Thoracic and Cardiovascular Surgery, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, No. 114, Tianjin Street, Huangshi, 435000, Hubei, P.R. China
| | - Zhanwen Sun
- Department of Thoracic and Cardiovascular Surgery, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, No. 114, Tianjin Street, Huangshi, 435000, Hubei, P.R. China
| | - Dengyun Wang
- Department of Thoracic and Cardiovascular Surgery, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, No. 114, Tianjin Street, Huangshi, 435000, Hubei, P.R. China
| | - Tian Du
- Department of Thoracic and Cardiovascular Surgery, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, No. 114, Tianjin Street, Huangshi, 435000, Hubei, P.R. China.
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26
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Enkhnaran B, Zhang GC, Zhang NP, Liu HN, Wu H, Xuan S, Yu XN, Song GQ, Shen XZ, Zhu JM, Liu XP, Liu TT. microRNA-106b-5p Promotes Cell Growth and Sensitizes Chemosensitivity to Sorafenib by Targeting the BTG3/Bcl-xL/p27 Signaling Pathway in Hepatocellular Carcinoma. JOURNAL OF ONCOLOGY 2022; 2022:1971559. [PMID: 35342408 PMCID: PMC8947873 DOI: 10.1155/2022/1971559] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 12/11/2021] [Accepted: 02/04/2022] [Indexed: 12/30/2022]
Abstract
microRNAs (miRNAs) and miRNA-mediated regulatory networks are promising candidates in the prevention and treatment of cancer, but the role of specific miRNAs involved in hepatocellular carcinoma (HCC) remains to be elusive. Herein, we found that miR-106b-5p is upregulated in both HCC patients' tumor tissues and HCC cell lines. The miR-106b-5p expression level was positively correlated with α-fetoprotein (AFP), hepatitis B surface antigen (HBsAg), and tumor size. Overexpression of miR-106b-5p promoted cell proliferation, migration, cell cycle G1/S transition, and tumor growth, while decreased miR-106b-5p expression had opposite effects. Mechanistic studies showed that B-cell translocation gene 3 (BTG3), a known antiproliferative protein, was a direct target of miR-106b-5p, whose expression level is inversely correlated with miR-106b-5p expression. Moreover, miR-106b-5p positively regulates cell proliferation in a BTG3-dependent manner, resulting in upregulation of Bcl-xL, cyclin E1, and CDK2, as well as downregulation of p27. More importantly, we also demonstrated that miR-106b-5p enhances the resistance to sorafenib treatment in a BTG3-dependent manner. The in vivo findings showed that mice treated with a miR-106b-5p sponge presented a smaller tumor burden than controls, while the mice injected cells treated with miR-106b-5p had more considerable tumor burden than controls. Altogether, these data suggest that miR-106b-5p promotes cell proliferation and cell cycle and increases HCC cells' resistance to sorafenib through the BTG3/Bcl-xL/p27 signaling pathway.
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Affiliation(s)
- Bilegsaikhan Enkhnaran
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Guang-Cong Zhang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Ning-Ping Zhang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Hai-Ning Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Hao Wu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Shi Xuan
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xiang-Nan Yu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Guang-Qi Song
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xi-Zhong Shen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Key Laboratory of Medical Molecular Virology, Shanghai Medical College of, Fudan University, Shanghai 200032, China
| | - Ji-Min Zhu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xiu-Ping Liu
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Tao-Tao Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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27
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Baymiller M, Nordick B, Forsyth CM, Martinis SA. Tissue-specific alternative splicing separates the catalytic and cell signaling functions of human leucyl-tRNA synthetase. J Biol Chem 2022; 298:101757. [PMID: 35202654 PMCID: PMC8941210 DOI: 10.1016/j.jbc.2022.101757] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 02/11/2022] [Accepted: 02/12/2022] [Indexed: 11/29/2022] Open
Abstract
The aminoacyl-tRNA synthetases are an ancient and ubiquitous component of all life. Many eukaryotic synthetases balance their essential function, preparing aminoacyl-tRNA for use in mRNA translation, with diverse roles in cell signaling. Herein, we use long-read sequencing to discover a leukocyte-specific exon skipping event in human leucyl-tRNA synthetase (LARS). We show that this highly expressed splice variant, LSV3, is regulated by serine-arginine-rich splicing factor 1 (SRSF1) in a cell-type-specific manner. LSV3 has a 71 amino acid deletion in the catalytic domain and lacks any tRNA leucylation activity in vitro. However, we demonstrate that this LARS splice variant retains its role as a leucine sensor and signal transducer for the proliferation-promoting mTOR kinase. This is despite the exon deletion in LSV3 including a portion of the previously mapped Vps34-binding domain used for one of two distinct pathways from LARS to mTOR. In conclusion, alternative splicing of LARS has separated the ancient catalytic activity of this housekeeping enzyme from its more recent evolutionary role in cell signaling, providing an opportunity for functional specificity in human immune cells.
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Affiliation(s)
- Max Baymiller
- Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, Illinois, USA
| | - Benjamin Nordick
- Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, Illinois, USA
| | - Connor M Forsyth
- Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, Illinois, USA
| | - Susan A Martinis
- Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, Illinois, USA.
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28
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Sun HY, Du ST, Li YY, Deng GT, Zeng FR. Bromodomain and extra-terminal inhibitors emerge as potential therapeutic avenues for gastrointestinal cancers. World J Gastrointest Oncol 2022; 14:75-89. [PMID: 35116104 PMCID: PMC8790409 DOI: 10.4251/wjgo.v14.i1.75] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 08/11/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancers, including colorectal cancer, pancreatic cancer, liver cancer and gastric cancer, are severe social burdens due to high incidence and mortality rates. Bromodomain and extra-terminal (BET) proteins are epigenetic readers consisting of four conserved members (BRD2, BRD3, BRD4 and BRDT). BET family perform pivotal roles in tumorigenesis through transcriptional regulation, thereby emerging as potential therapeutic targets. BET inhibitors, disrupting the interaction between BET proteins and acetylated lysines, have been reported to suppress tumor initiation and progression in most of GI cancers. In this review, we will demonstrate how BET proteins participate in the GI cancers progression and highlight the therapeutic potential of targeting BET proteins for GI cancers treatment.
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Affiliation(s)
- Hui-Yan Sun
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Song-Tao Du
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Colorectal Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Ya-Yun Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Guang-Tong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Fu-Rong Zeng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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Transcriptomic Crosstalk between Gliomas and Telencephalic Neural Stem and Progenitor Cells for Defining Heterogeneity and Targeted Signaling Pathways. Int J Mol Sci 2021; 22:ijms222413211. [PMID: 34948008 PMCID: PMC8703403 DOI: 10.3390/ijms222413211] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 11/29/2021] [Accepted: 11/30/2021] [Indexed: 12/15/2022] Open
Abstract
Recent studies have begun to reveal surprising levels of cell diversity in the human brain, both in adults and during development. Distinctive cellular phenotypes point to complex molecular profiles, cellular hierarchies and signaling pathways in neural stem cells, progenitor cells, neuronal and glial cells. Several recent reports have suggested that neural stem and progenitor cell types found in the developing and adult brain share several properties and phenotypes with cells from brain primary tumors, such as gliomas. This transcriptomic crosstalk may help us to better understand the cell hierarchies and signaling pathways in both gliomas and the normal brain, and, by clarifying the phenotypes of cells at the origin of the tumor, to therapeutically address their most relevant signaling pathways.
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MiR-106b-5p Promotes Malignant Behaviors of Cervical Squamous Cell Carcinoma Cells by Targeting TIMP2. Reprod Sci 2021; 29:203-211. [PMID: 34767243 DOI: 10.1007/s43032-021-00788-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 10/30/2021] [Indexed: 10/19/2022]
Abstract
The objective of this study was to investigate modulatory mechanism of miR-106b-5p and tissue inhibitor of metalloproteinases 2 (TIMP2) on cervical squamous cell carcinoma cells. Differentially expressed genes in CSCC were analyzed via bioinformatics analysis. The targeting impact of miR-106b-5p on TIMP2 was validated through dual-luciferase assay and RNA immunoprecipitation assay. MiR-106b-5p level and TIMP2 mRNA level were assessed via qRT-PCR. TIMP2 protein level was measured via western blot. Malignant behaviors of CSCC cells were evaluated by functional experiments. The EMT and apoptosis-related proteins were determined via western blot. MiR-106b-5p was noticeably elevated in CSCC cells. Its downstream target was TIMP2. MiR-106b-5p and TIMP2 levels were inversely correlated. MiR-106b-5p overexpression fostered malignant phenotypes of CSCC cells, and vice versus. TIMP2 overexpression weakened the promotive impact of forced expression of miR-106b-5p on CSCC cell growth. EMT was facilitated by forced expression of miR-106b-5p. MiR-106b-5p regulates the progression of CSCC cells via targeting TIMP2, which may provide novel value for development of therapeutic targets for CSCC.
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31
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Liao X, Qian X, Zhang Z, Tao Y, Li Z, Zhang Q, Liang H, Li X, Xie Y, Zhuo R, Chen Y, Jiang Y, Cao H, Niu J, Xue C, Ni J, Pan J, Cui D. ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways. Front Oncol 2021; 11:753119. [PMID: 34733788 PMCID: PMC8559897 DOI: 10.3389/fonc.2021.753119] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 09/27/2021] [Indexed: 01/20/2023] Open
Abstract
Objective Suppression of bromodomain and extra terminal (BET) proteins has a bright prospect to treat MYC-driven tumors. Bromodomain containing 4 (BRD4) is one of the BET proteins. ARV-825, consisting of a BRD4 inhibitor conjugated with a cereblon ligand using proteolysis-targeting chimera (PROTAC) technology, was proven to decrease the tumor growth effectively and continuously. Nevertheless, the efficacy and mechanisms of ARV-825 in gastric cancer are still poorly understood. Methods Cell counting kit 8 assay, lentivirus infection, Western blotting analysis, Annexin V/propidium iodide (PI) staining, RNA sequencing, a xenograft model, and immunohistochemistry were used to assess the efficacy of ARV-825 in cell level and animal model. Results The messenger RNA (mRNA) expression of BRD4 in gastric cancer raised significantly than those in normal tissues, which suggested poor outcome of patients with gastric cancer. ARV-825 displayed higher anticancer efficiency in gastric cancer cells than OTX015 and JQ1. ARV-825 could inhibit cell growth, inducing cell cycle block and apoptosis in vitro. ARV-825 induced degradation of BRD4, BRD2, BRD3, c-MYC, and polo-like kinase 1 (PLK1) proteins in four gastric cancer cell lines. In addition, cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP) was elevated. Knockdown or overexpression CRBN could increase or decrease, respectively, the ARV-825 IC50 of gastric cancer cells. ARV-825 reduced MYC and PLK1 expression in gastric cancer cells. ARV-825 treatment significantly reduced tumor growth without toxic side effects and downregulated the expression of BRD4 in vivo. Conclusions High mRNA expression of BRD4 in gastric cancer indicated poor prognosis. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells via transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.
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Affiliation(s)
- Xinmei Liao
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoqing Qian
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China.,School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Zimu Zhang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Yanfang Tao
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Zhiheng Li
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Qian Zhang
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Hui Liang
- Institute of Nanomedicine, National Engineering Research Centre for Nanotechnology, Shanghai, China
| | - Xiaolu Li
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Yi Xie
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Ran Zhuo
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Yanling Chen
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - You Jiang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Haibo Cao
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Jiaqi Niu
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Cuili Xue
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Jian Ni
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Jian Pan
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Daxiang Cui
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China.,Institute of Nanomedicine, National Engineering Research Centre for Nanotechnology, Shanghai, China
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Footprints of microRNAs in Cancer Biology. Biomedicines 2021; 9:biomedicines9101494. [PMID: 34680611 PMCID: PMC8533183 DOI: 10.3390/biomedicines9101494] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/19/2021] [Accepted: 09/21/2021] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs involved in post-transcriptional gene regulation. Over the past years, various studies have demonstrated the role of aberrant miRNA expression in the onset of cancer. The mechanisms by which miRNA exerts its cancer-promoting or inhibitory effects are apparent through the various cancer hallmarks, which include selective proliferative advantage, altered stress response, vascularization, invasion and metastasis, metabolic rewiring, the tumor microenvironment and immune modulation; therefore, this review aims to highlight the association between miRNAs and the various cancer hallmarks by dissecting the mechanisms of miRNA regulation in each hallmark separately. It is hoped that the information presented herein will provide further insights regarding the role of cancer and serve as a guideline to evaluate the potential of microRNAs to be utilized as biomarkers and therapeutic targets on a larger scale in cancer research.
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33
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Feng L, Wang G, Chen Y, He G, Liu B, Liu J, Chiang CM, Ouyang L. Dual-target inhibitors of bromodomain and extra-terminal proteins in cancer: A review from medicinal chemistry perspectives. Med Res Rev 2021; 42:710-743. [PMID: 34633088 DOI: 10.1002/med.21859] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 07/14/2021] [Accepted: 09/26/2021] [Indexed: 02/05/2023]
Abstract
Bromodomain-containing protein 4 (BRD4), as the most studied member of the bromodomain and extra-terminal (BET) family, is a chromatin reader protein interpreting epigenetic codes through binding to acetylated histones and non-histone proteins, thereby regulating diverse cellular processes including cell cycle, cell differentiation, and cell proliferation. As a promising drug target, BRD4 function is closely related to cancer, inflammation, cardiovascular disease, and liver fibrosis. Currently, clinical resistance to BET inhibitors has limited their applications but synergistic antitumor effects have been observed when used in combination with other tumor inhibitors targeting additional cellular components such as PLK1, HDAC, CDK, and PARP1. Therefore, designing dual-target inhibitors of BET bromodomains is a rational strategy in cancer treatment to increase potency and reduce drug resistance. This review summarizes the protein structures and biological functions of BRD4 and discusses recent advances of dual BET inhibitors from a medicinal chemistry perspective. We also discuss the current design and discovery strategies for dual BET inhibitors, providing insight into potential discovery of additional dual-target BET inhibitors.
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Affiliation(s)
- Lu Feng
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
| | - Guan Wang
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
| | - Yi Chen
- State Key Laboratory of Biotherapy and Cancer Center and Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Gu He
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
| | - Bo Liu
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
| | - Jie Liu
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
| | - Cheng-Ming Chiang
- Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Liang Ouyang
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
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34
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Ling B, Liao X, Tang Q, Ye G, Bin X, Wang J, Pang Y, Qi G. MicroRNA-106b-5p inhibits growth and progression of lung adenocarcinoma cells by downregulating IGSF10. Aging (Albany NY) 2021; 13:18740-18756. [PMID: 34351868 PMCID: PMC8351668 DOI: 10.18632/aging.203318] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 05/18/2021] [Indexed: 12/04/2022]
Abstract
In this study, we investigated the mechanistic role and prognostic significance of IGSF10 in lung adenocarcinoma. Oncomine database analysis showed that IGSF10 expression was significantly reduced in most cancer types, including lung adenocarcinoma (LUAD). In the TCGA-LUAD dataset, IGSF10 expression correlated positively with proportions of tumor-infiltrated B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells. Kaplan-Meier survival analysis showed that overall survival of patients with low IGSF10 expression was significantly shorter than those with high IGSF10 expression. MiRWalk2.0 database analysis and dual luciferase reporter assays confirmed that miR-106b-5p suppressed IGSF10 expression by binding to its 3’UTR. MiR-106b-5p levels inversely correlated with IGSF10 expression in the TCGA-LUAD dataset. Moreover, inhibition of miR-106b-5p significantly decreased in vitro proliferation, migration, and invasion by LUAD cells, whereas miR-106b-5p overexpression reversed those effects. These results demonstrate that IGSF10 is an independent prognostic factor for LUAD. Furthermore, miR-106b-5p suppressed IGSF10 expression in LUAD tissues by binding to its 3’UTR, which makes IGSF10 and miR-106b-5p potential prognostic biomarkers and therapeutic targets in LUAD patients.
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Affiliation(s)
- Bo Ling
- College of Pharmacy, Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Xianjiu Liao
- College of Pharmacy, Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Qiang Tang
- Department of Burn and Plastic Surgery and Wound Repair, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Guangbin Ye
- College of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China.,Medical College of Guangxi University, Nanning 530004, Guangxi, China
| | - Xiaoyun Bin
- College of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Jianchu Wang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Yaqin Pang
- College of Medical Laboratory, Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Guangzi Qi
- College of Public Health and Management, Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
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35
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Jing C, Liu D, Lai Q, Li L, Zhou M, Ye B, Wu Y, Li H, Yue K, Wu Y, Duan Y, Wang X. JOSD1 promotes proliferation and chemoresistance of head and neck squamous cell carcinoma under the epigenetic regulation of BRD4. Cancer Cell Int 2021; 21:375. [PMID: 34261480 PMCID: PMC8278721 DOI: 10.1186/s12935-021-02060-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 06/27/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Deubiquitinating enzymes (DUBs) play critical roles in various cancers by modulating functional proteins post-translationally. Previous studies have demonstrated that DUB Josephin Domain Containing 1 (JOSD1) is implicated in tumor progression, however, the role and mechanism of JOSD1 in head and neck squamous cell carcinoma (HNSCC) remain to be explored. In this study, we aimed to identify the clinical significance and function of JOSD1 in HNSCC. METHODS The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed to find novel DUBs in HNSCC. Immunohistochemistry assay was performed to determine the expression of JOSD1 in our cohort of 42 patients suffered with HNSCC. Kaplan-Meier analysis was used to identify the correlation between JOSD1 and the prognosis of HNSCC patients. The regulation of BRD4 on JOSD1 was determined by using pharmacological inhibition and gene depletion. The in vitro and in vivo experiments were conducted to elucidate the role of JOSD1 in HNSCC. RESULTS The results of IHC showed that JOSD1 was aberrantly expressed in HNSCC specimens, especially in the chemoresistant ones. The overexpression of JOSD1 indicated poor clinical outcome of HNSCC patients. Moreover, JOSD1 depletion dramatically impaired cell proliferation and colony formation, and promoted cisplatin-induced apoptosis of HNSCC cells in vitro. Additionally, JOSD1 suppression inhibited the tumor growth and improved chemosensitivity in vivo. The epigenetic regulator BRD4 contributed to the upregulation of JOSD1 in HNSCC. CONCLUSIONS These results demonstrate that JOSD1 functions as an oncogene in HNSCC progression, and provide a promising target for clinical diagnosis and therapy of HNSCC.
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Affiliation(s)
- Chao Jing
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Dandan Liu
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Qingchuan Lai
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Linqi Li
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Mengqian Zhou
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Beibei Ye
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yue Wu
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Hong Li
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Kai Yue
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yansheng Wu
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China.
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
| | - Yuansheng Duan
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China.
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
| | - Xudong Wang
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China.
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
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Bi H, Shang J, Zou X, Xu J, Han Y. Palbociclib induces cell senescence and apoptosis of gastric cancer cells by inhibiting the Notch pathway. Oncol Lett 2021; 22:603. [PMID: 34188705 PMCID: PMC8227472 DOI: 10.3892/ol.2021.12864] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 04/08/2021] [Indexed: 12/24/2022] Open
Abstract
Palbociclib (PD0332991), a selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has been reported to exert anticancer activity in some cancers, including gastric cancer (GC). However, the role of palbociclib in GC remains largely unknown. The present study aimed to investigate the effects of palbociclib on the progression of GC and the potential mechanisms underlying its effects. The colony formation, proliferation, senescence, as well as apoptosis and cell cycle progression of AGS and HGC-27 cells following treatment with palbociclib were analyzed using colony formation assays, MTT assays, senescence-associated β-galactosidase (SA-β-gal) staining and flow cytometry, respectively. The protein expression levels of Bax, Caspase-3, Bcl-2, p16, p21, p53, Notch1, Notch2 and hairy and enhancer of split 1 (Hes1) were measured in AGS and HGC-27 cells using western blotting. Moreover, the mRNA expression levels of Notch1, Notch2 and Hes1 in AGS and HGC-27 cells were determined by reverse transcription-quantitative PCR. In the present study, palbociclib significantly inhibited cell proliferation and induced cell senescence, cell cycle arrest and apoptosis in both cell lines in a dose-dependent manner. Additionally, palbociclib significantly increased the expression levels of Bax, Caspase-3, p16, p21 and p53, whilst decreasing the expression of Bcl-2, Notch1, Notch2 and Hes1 in AGS and HGC-27 cells. Furthermore, the Notch pathway activator Jagged-1/FC reversed the effects of palbociclib on cell proliferation, apoptosis, senescence and cell cycle progression. These findings demonstrated that palbociclib could inhibit proliferation and induce senescence, cell cycle arrest and apoptosis in GC cells by inhibiting the Notch pathway.
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Affiliation(s)
- Hengtai Bi
- Department of Pharmacy, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
| | - Juan Shang
- Department of Pharmacy, The People's Hospital of Bin Zhou, Bin Zhou, Shandong 256600, P.R. China
| | - Xiao Zou
- Department of Oncology, The First People's Hospital of Tai'an, Tai'an, Shandong 271000, P.R. China
| | - Jing Xu
- Department of Neurology, The First People's Hospital of Tai'an, Tai'an, Shandong 271000, P.R. China
| | - Yumei Han
- Department of General Surgery, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
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Jiang S, Ren X, Liu S, Lu Z, Xu A, Qin C, Wang Z. Integrated Analysis of the Prognosis-Associated RNA-Binding Protein Genes and Candidate Drugs in Renal Papillary Cell Carcinoma. Front Genet 2021; 12:627508. [PMID: 33643390 PMCID: PMC7907657 DOI: 10.3389/fgene.2021.627508] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 01/20/2021] [Indexed: 12/13/2022] Open
Abstract
RNA-binding proteins (RBPs) play significant roles in various cancer types. However, the functions of RBPs have not been clarified in renal papillary cell carcinoma (pRCC). In this study, we identified 31 downregulated and 89 upregulated differentially expressed RBPs on the basis of the cancer genome atlas (TCGA) database and performed functional enrichment analyses. Subsequently, through univariate Cox, random survival forest, and multivariate Cox regression analysis, six RBPs of SNRPN, RRS1, INTS8, RBPMS2, IGF2BP3, and PIH1D2 were screened out, and the prognostic model was then established. Further analyses revealed that the high-risk group had poor overall survival. The area under the curve values were 0.87 and 0.75 at 3 years and 0.78 and 0.69 at 5 years in the training set and test set, respectively. We then plotted a nomogram on the basis of the six RBPs and tumor stage with the substantiation in the TCGA cohort. Moreover, we selected two intersectant RBPs and evaluate their biological effects by GSEA and predicted three drugs, including STOCK1N-28457, pyrimethamine, and trapidil by using the Connectivity Map. Our research provided a novel insight into pRCC and improved the determination of prognosis and individualized therapeutic strategies.
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Affiliation(s)
- Silin Jiang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaohan Ren
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shouyong Liu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhongwen Lu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Aiming Xu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chao Qin
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zengjun Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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38
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Chen W, Zhang K, Yang Y, Guo Z, Wang X, Teng B, Zhao Q, Huang C, Qiu Z. MEF2A-mediated lncRNA HCP5 Inhibits Gastric Cancer Progression via MiR-106b-5p/p21 Axis. Int J Biol Sci 2021; 17:623-634. [PMID: 33613117 PMCID: PMC7893594 DOI: 10.7150/ijbs.55020] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 12/31/2020] [Indexed: 12/16/2022] Open
Abstract
Background: Long non-coding RNAs (lncRNAs) are deemed to be relevant to the tumorigenesis and development of a variety of tumors, containing gastric cancer (GC). The purpose of our investigations is to explore the character of HCP5 in GC. Methods: HCP5 expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in 62 matched GC tissues and corresponding para-carcinoma tissues. In vitro and in vivo functional assays were subjected to verify the biological effects of HCP5 after alteration of HCP5. Chromatin immunoprecipitation assay (CHIP) assays were conducted to confirm that myocyte enhancer factor 2A (MEF2A) could bind to HCP5 promoter regions and thereby induce HCP5 expression. Analysis of the latent binding of miR-106b-5p to HCP5 and p21 was made by bioinformatics prediction and luciferase reporter assays. Results: Significant downregulation of HCP5 was detected in GC tissues. Negative correlation was determined between HCP5 expression level and tumor size and overall survival in GC patients. HCP5 depletion had a facilitating impact on proliferation, migration and invasion of GC cells. Consistently, overexpression of HCP5 came into an opposite effect. Moreover, we demonstrated that MEF2A could combine with the promoter region of HCP5 and thereby induce HCP5 transcription. Luciferase reporter assays revealed that HCP5 could compete with miR-106b-5p as a competing endogenous RNA (ceRNA) and upregulated p21 expression in GC. Conclusions: MEF2A-mediated HCP5 could exert an anti-tumor effect among the development of GC via miR-106b-5p/p21 axis, which provides a novel target for GC therapy.
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Affiliation(s)
- Weiwei Chen
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, 201600, China
| | - Kundong Zhang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, 201600, China
| | - Yuhan Yang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, 201600, China
| | - Zengya Guo
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, 201600, China
| | - Xiaofeng Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, 201600, China
| | - Buwei Teng
- Lianyungang Clinical College of Nanjing Medical University/The First People's Hospital of Lianyungang, 6 Zhenhua East Road, Haizhou District, City of Lianyungang, Jiangsu Province, 222061, China
| | - Qian Zhao
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Chen Huang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, 201600, China
| | - Zhengjun Qiu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, 201600, China
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39
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Identifying of biomarkers associated with gastric cancer based on 11 topological analysis methods of CytoHubba. Sci Rep 2021; 11:1331. [PMID: 33446695 PMCID: PMC7809423 DOI: 10.1038/s41598-020-79235-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Accepted: 12/02/2020] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is one of the most common types of malignancy. Its potential molecular mechanism has not been clarified. In this study, we aimed to explore potential biomarkers and prognosis-related hub genes associated with GC. The gene chip dataset GSE79973 was downloaded from the GEO datasets and limma package was used to identify the differentially expressed genes (DEGs). A total of 1269 up-regulated and 330 down-regulated genes were identified. The protein-protein interactions (PPI) network of DEGs was constructed by STRING V11 database, and 11 hub genes were selected through intersection of 11 topological analysis methods of CytoHubba in Cytoscape plug-in. All the 11 selected hub genes were found in the module with the highest score from PPI network of all DEGs by the molecular complex detection (MCODE) clustering algorithm. In order to explore the role of the 11 hub genes, we performed GO function and KEGG pathway analysis for them and found that the genes were enriched in a variety of functions and pathways among which cellular senescence, cell cycle, viral carcinogenesis and p53 signaling pathway were the most associated with GC. Kaplan-Meier analysis revealed that 10 out of the 11 hub genes were related to the overall survival of GC patients. Further, seven of the 11 selected hub genes were verified significantly correlated with GC by uni- or multivariable Cox model and LASSO regression analysis including C3, CDK1, FN1, CCNB1, CDC20, BUB1B and MAD2L1. C3, CDK1, FN1, CCNB1, CDC20, BUB1B and MAD2L1 may serve as potential prognostic biomarkers and therapeutic targets for GC.
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40
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Shi C, Yang EJ, Liu Y, Mou PK, Ren G, Shim JS. Bromodomain and extra-terminal motif (BET) inhibition is synthetic lethal with loss of SMAD4 in colorectal cancer cells via restoring the loss of MYC repression. Oncogene 2020; 40:937-950. [PMID: 33293694 DOI: 10.1038/s41388-020-01580-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 02/07/2023]
Abstract
The tumor suppressor SMAD4 is frequently mutated in colorectal cancer (CRC). However, no effective targeted therapies exist for CRC with SMAD4 loss. Here, we employed a synthetic lethality drug screening in isogenic SMAD4+/+ and SMAD4-/- HCT116 CRC cells and found that bromodomain and extra-terminal motif (BET) inhibitors, as selective drugs for the growth of SMAD4-/- HCT116 cells. BET inhibition selectively induced G1 cell cycle arrest in SMAD4-/- cells and this effect was accompanied by the reprogramming of the MYC-p21 axis. Mechanistically, SMAD4 is a transcription repressor of MYC, and MYC in turn represses p21 transcription. SMAD4-/- cells lost MYC repression ability, thereby causing the cells addicted to the MYC oncogenic signaling. BET inhibition significantly reduced MYC level and restored p21 expression in SMAD4-/- cells, inducing the selective growth arrest. The ectopic overexpression of MYC or the silencing of p21 could rescue the BET inhibitor-induced growth arrest in SMAD4-/- cells, verifying this model. Tumor xenograft mouse experiments further demonstrated the synthetic lethality interaction between BET and SMAD4 in vivo. Taken together, our data suggest that BET could be a potential drug target for the treatment of SMAD4-deficient CRC.
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Affiliation(s)
- Changxiang Shi
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China
| | - Eun Ju Yang
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China
| | - Yifan Liu
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China
| | - Pui Kei Mou
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China
| | - Guowen Ren
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China
| | - Joong Sup Shim
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China.
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41
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Li T, Mao C, Wang X, Shi Y, Tao Y. Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:224. [PMID: 33109235 PMCID: PMC7592369 DOI: 10.1186/s13046-020-01733-5] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023]
Abstract
Hypoxia is the major influence factor in physiological and pathological courses which are mainly mediated by hypoxia-inducible factors (HIFs) in response to low oxygen tensions within solid tumors. Under normoxia, HIF signaling pathway is inhibited due to HIF-α subunits degradation. However, in hypoxic conditions, HIF-α is activated and stabilized, and HIF target genes are successively activated, resulting in a series of tumour-specific activities. The activation of HIFs, including HIF-1α, HIF-2α and HIF-3α, subsequently induce downstream target genes which leads to series of responses, the resulting abnormal processes or metabolites in turn affect HIFs stability. Given its functions in tumors progression, HIFs have been regarded as therapeutic targets for improved treatment efficacy. Epigenetics refers to alterations in gene expression that are stable between cell divisions, and sometimes between generations, but do not involve changes in the underlying DNA sequence of the organism. And with the development of research, epigenetic regulation has been found to play an important role in the development of tumors, which providing accumulating basic or clinical evidences for tumor treatments. Here, given how little has been reported about the overall association between hypoxic tumors and epigenetics, we made a more systematic review from epigenetic perspective in hope of helping others better understand hypoxia or HIF pathway, and providing more established and potential therapeutic strategies in tumors to facilitate epigenetic studies of tumors.
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Affiliation(s)
- Tiansheng Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Chao Mao
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Xiang Wang
- Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Ying Shi
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China. .,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.
| | - Yongguang Tao
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China. .,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China. .,Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, China.
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42
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Xu JL, Yuan YJ, Lv J, Qi D, Wu MD, Lan J, Liu SN, Yang Y, Zhai J, Jiang HM. Inhibition of BRD4 triggers cellular senescence through suppressing aurora kinases in oesophageal cancer cells. J Cell Mol Med 2020; 24:13036-13045. [PMID: 32954665 PMCID: PMC7701500 DOI: 10.1111/jcmm.15901] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 08/22/2020] [Accepted: 09/01/2020] [Indexed: 01/16/2023] Open
Abstract
Oesophageal cancer is one of the most frequent solid malignancies and the leading cause of cancer-related death around the world. It is urgent to develop novel therapy strategies to improve patient outcomes. Acetylation modification of histones has been extensively studied in epigenetics. BRD4, a reader of acetylated histone and non-histone proteins, has involved in tumorigenesis. It has emerged as a promising target for cancer therapy. BRD4 inhibitors, such as JQ1, have exerted efficacious anti-proliferation activities in diverse cancers. However, the effects of JQ1 on oesophageal cancer are still not fully described. Here, we demonstrate that JQ1 suppresses cell growth and triggers cellular senescence in KYSE450 cells. Mechanistically, JQ1 up-regulates p21 level and decreases cyclin D1 resulting in G1 cycle arrest. The inhibitory effects of JQ1 on KYSE450 cells are independent on apoptosis. It activates cellular senescence by increasing SA-β-gal activity. BRD4 knockdown by shRNA recapitulates cellular senescence. We also display that administration of JQ1 decreases recruitment of BRD4 on the promoter of aurora kinases A and B. Inhibitors targeting at AURKA/B phenocopy JQ1 treatment in KYSE450 cells. These results identify a novel action manner of BRD4 in oesophageal cancer, which strengthens JQ1 as a candidate drug in oesophageal cancer chemotherapy.
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Affiliation(s)
- Jian-Ling Xu
- Department of Biochemistry, School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Ya-Jiao Yuan
- Department of Biochemistry, School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.,Department of Clinical Laboratory, People's Hospital of Jimo District, Qingdao, China
| | - Jiao Lv
- Department of Biochemistry, School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Di Qi
- Department of Biochemistry, School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Meng-Di Wu
- Department of Biochemistry, School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Jing Lan
- Department of Biochemistry, School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Sheng-Nan Liu
- Department of Biochemistry, School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Yong Yang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Shandong First Medical University, Taian, China
| | - Jing Zhai
- Department of Biochemistry, School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Han-Ming Jiang
- Department of Biochemistry, School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
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43
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Couturier CP, Ayyadhury S, Le PU, Nadaf J, Monlong J, Riva G, Allache R, Baig S, Yan X, Bourgey M, Lee C, Wang YCD, Wee Yong V, Guiot MC, Najafabadi H, Misic B, Antel J, Bourque G, Ragoussis J, Petrecca K. Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy. Nat Commun 2020; 11:3406. [PMID: 32641768 PMCID: PMC7343844 DOI: 10.1038/s41467-020-17186-5] [Citation(s) in RCA: 303] [Impact Index Per Article: 60.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 06/17/2020] [Indexed: 02/07/2023] Open
Abstract
Cancer stem cells are critical for cancer initiation, development, and treatment resistance. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To overcome these limitations, we performed single-cell RNA sequencing on 53586 adult glioblastoma cells and 22637 normal human fetal brain cells, and compared the lineage hierarchy of the developing human brain to the transcriptome of cancer cells. We find a conserved neural tri-lineage cancer hierarchy centered around glial progenitor-like cells. We also find that this progenitor population contains the majority of the cancer's cycling cells, and, using RNA velocity, is often the originator of the other cell types. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, suggests a possible origin for glioblastoma hierarchy, and helps to identify cancer stem cell-specific targets.
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Affiliation(s)
- Charles P Couturier
- Department of Neurosciences, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada
| | - Shamini Ayyadhury
- Department of Neurosciences, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada
| | - Phuong U Le
- Department of Neurosciences, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada
| | - Javad Nadaf
- Department of Neurosciences, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- McGill University and Genome Québec Innovation Centre, Montreal, QC, Canada
| | - Jean Monlong
- Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Gabriele Riva
- Department of Neurosciences, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada
| | - Redouane Allache
- Department of Neurosciences, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada
| | - Salma Baig
- Department of Neurosciences, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada
| | - Xiaohua Yan
- Department of Neurosciences, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada
| | - Mathieu Bourgey
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- McGill University and Genome Québec Innovation Centre, Montreal, QC, Canada
- Canadian Centre for Computational Genomics, McGill University, Montreal, QC, Canada
| | - Changseok Lee
- Department of Neurosciences, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada
| | - Yu Chang David Wang
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- McGill University and Genome Québec Innovation Centre, Montreal, QC, Canada
| | - V Wee Yong
- Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
| | - Marie-Christine Guiot
- Department of Neuropathology, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
| | - Hamed Najafabadi
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- McGill University and Genome Québec Innovation Centre, Montreal, QC, Canada
| | - Bratislav Misic
- Department of Neurosciences, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada
| | - Jack Antel
- Department of Neurosciences, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada
| | - Guillaume Bourque
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- McGill University and Genome Québec Innovation Centre, Montreal, QC, Canada
- Canadian Centre for Computational Genomics, McGill University, Montreal, QC, Canada
| | - Jiannis Ragoussis
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- McGill University and Genome Québec Innovation Centre, Montreal, QC, Canada
- Department of Bioengineering, McGill University, Montreal, QC, Canada
| | - Kevin Petrecca
- Department of Neurosciences, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada.
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44
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Yang C, Dou R, Yin T, Ding J. MiRNA-106b-5p in human cancers: diverse functions and promising biomarker. Biomed Pharmacother 2020; 127:110211. [PMID: 32422566 DOI: 10.1016/j.biopha.2020.110211] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 04/19/2020] [Accepted: 04/28/2020] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs), as a class of small, well-conserved, non-coding RNA molecules, hold the capacity to post-transcriptionally suppress the expression of over 50% protein-coding genes. Emerging and accumulating evidence suggests that miRNAs function as the master regulators of multiple pathophysiological processes, and play important roles in diverse human diseases, especially in tumorigenesis and progression. MiR-106b-5p, a member of miR-106b seed family, has been demonstrated to be aberrantly expressed in human solid malignancies, and to play paradoxically opposing functions as an oncomiR or a tumor suppressor in tumor development. In addition, it has been recently reported to be a promising biomarker for prognostic evaluation for cancer patients. In the present review, we provided an overview to summarize the present findings of miR-106b-5p in cancer research fields, thereby establishing comprehensive understanding of its diverse functions and clinical implications in human cancers.
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Affiliation(s)
- Chaogang Yang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China; Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, 430071, China; Hubei Cancer Clinical Study Center, Wuhan, 430071, China
| | - Rongzhang Dou
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China; Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, 430071, China; Hubei Cancer Clinical Study Center, Wuhan, 430071, China
| | - Tailang Yin
- Reproductive Medical Center, Renmin Hospital of Wuhan University, Wuhan, 430060, China; Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, 430060, China.
| | - Jinli Ding
- Reproductive Medical Center, Renmin Hospital of Wuhan University, Wuhan, 430060, China; Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, 430060, China.
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45
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Zhou S, Zhang S, Wang L, Huang S, Yuan Y, Yang J, Wang H, Li X, Wang P, Zhou L, Yang J, Xu Y, Gao H, Zhang Y, Lv Y, Zou X. BET protein inhibitor JQ1 downregulates chromatin accessibility and suppresses metastasis of gastric cancer via inactivating RUNX2/NID1 signaling. Oncogenesis 2020; 9:33. [PMID: 32157097 PMCID: PMC7064486 DOI: 10.1038/s41389-020-0218-z] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 02/25/2020] [Accepted: 02/26/2020] [Indexed: 02/06/2023] Open
Abstract
Chromatin accessibility is critical for tumor development, whose mechanisms remain unclear. As a crucial regulator for chromatin remodeling, BRD4 promotes tumor progression by regulating multiple genes. As a small-molecule inhibitor of BRD4, JQ1 has potent chemotherapeutic activity against various human cancers. However, whether JQ1 has potential anti-tumor effects and how JQ1 regulates global transcription in gastric cancer (GC) remain largely unknown. In this research, we found BRD4 was highly expressed in GC tissues and was significantly associated with poor prognosis. JQ1 inhibited the proliferation and induced apoptosis of GC cells in vitro. Besides, JQ1 suppressed the migration and invasion of cancer cells by inducing MET. Notably, an assay for transposase-accessible chromatin using sequencing (ATAC-seq) data showed that JQ1 obviously downregulated the chromatin accessibility of GC cells and differentially accessible regions were highly enriched for RUNX2-binding motifs. Combinational analysis of ATAC-seq and RNA-seq data discovered NID1 as the downstream target of JQ1 and JQ1 reduced NID1 expression in GC cells. Chromatin immunoprecipitation, luciferase reporter gene assay, and rescue experiments all confirmed that RUNX2/NID1 axis was responsible for JQ1-inhibiting metastasis of GC cells. What’s more, high expression of NID1 in GC tissues also predicted poor survival outcome of cancer patients and NID1 knockdown prohibited migration and invasion of cancer cells via partially inducing MET. Finally, in vivo models showed that JQ1 prevented GC growth and suppressed cancer metastasis. In conclusion, JQ1 inhibits the malignant progression of GC by downregulating chromatin accessibility and inactivating RUNX2/NID1 signaling. In addition, NID1 is also a novel therapeutic target for progressive GC patients.
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Affiliation(s)
- Siqi Zhou
- Department of Gastroenterology, Nanjing Medical University Affiliated Drum Tower Clinical Medical College, Nanjing, 210008, China.,Jiangsu Clinical Medical Center of Digestive Diseases, Nanjing, Jiangsu, China
| | - Shu Zhang
- Jiangsu Clinical Medical Center of Digestive Diseases, Nanjing, Jiangsu, China. .,Department of Gastroenterology, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, 210008, China.
| | - Lei Wang
- Jiangsu Clinical Medical Center of Digestive Diseases, Nanjing, Jiangsu, China.,Department of Gastroenterology, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, 210008, China
| | - Shuling Huang
- Jiangsu Clinical Medical Center of Digestive Diseases, Nanjing, Jiangsu, China.,Department of Gastroenterology, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, 210008, China
| | - Yue Yuan
- Department of Gastroenterology, Nanjing Medical University Affiliated Drum Tower Clinical Medical College, Nanjing, 210008, China.,Jiangsu Clinical Medical Center of Digestive Diseases, Nanjing, Jiangsu, China
| | - Jie Yang
- Department of Gastroenterology, Nanjing Medical University Affiliated Drum Tower Clinical Medical College, Nanjing, 210008, China.,Jiangsu Clinical Medical Center of Digestive Diseases, Nanjing, Jiangsu, China
| | - Hui Wang
- Jiangsu Clinical Medical Center of Digestive Diseases, Nanjing, Jiangsu, China.,Department of Gastroenterology, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, 210008, China
| | - Xihan Li
- Jiangsu Clinical Medical Center of Digestive Diseases, Nanjing, Jiangsu, China.,Department of Gastroenterology, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, 210008, China
| | - Pin Wang
- Jiangsu Clinical Medical Center of Digestive Diseases, Nanjing, Jiangsu, China.,Department of Gastroenterology, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, 210008, China
| | - Lin Zhou
- Jiangsu Clinical Medical Center of Digestive Diseases, Nanjing, Jiangsu, China.,Department of Gastroenterology, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, 210008, China
| | - Jun Yang
- Department of Pathology, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, 210008, China
| | - Yuemei Xu
- Department of Pathology, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, 210008, China
| | - Huan Gao
- Life Science Department, Vazyme Biotech Co., Nanjing State Economy and Technology Development Zone, Nanjing, 210000, China
| | - Yixuan Zhang
- Jiangsu Clinical Medical Center of Digestive Diseases, Nanjing, Jiangsu, China.,Department of Gastroenterology, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, 210008, China
| | - Ying Lv
- Jiangsu Clinical Medical Center of Digestive Diseases, Nanjing, Jiangsu, China. .,Department of Gastroenterology, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, 210008, China.
| | - Xiaoping Zou
- Department of Gastroenterology, Nanjing Medical University Affiliated Drum Tower Clinical Medical College, Nanjing, 210008, China. .,Jiangsu Clinical Medical Center of Digestive Diseases, Nanjing, Jiangsu, China.
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Tenhunen J, Kokkola T, Huovinen M, Rahnasto-Rilla M, Lahtela-Kakkonen M. Impact of structurally diverse BET inhibitors on SIRT1. Gene 2020; 741:144558. [PMID: 32165310 DOI: 10.1016/j.gene.2020.144558] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 03/08/2020] [Indexed: 12/15/2022]
Abstract
The epigenetic regulation of gene expression is controlled by various processes, of which one is histone acetylation. Many proteins control gene expression via histone acetylation. Those proteins include sirtuins (SIRTs) and bromodomain and extraterminal proteins (BETs), which are known to regulate same cellular processes and pathways. The aim of this study was to explore BET inhibitors' effects on SIRT1. Previously we showed that BET inhibitor (+)-JQ1 increases SIRT1 levels, but in the current study we used also other, structurally diverse BET inhibitors, I-BET151 and Pfi-1, and examined their effects on SIRT1 levels in two breast cancer cell lines. The results differed between the inhibitors and also between the cell lines. (+)-JQ1 had opposite effects on SIRT1 levels in the two cell lines, I-BET151 increased the levels in both cell lines, and Pfi-1 had no effect. In conclusion, the effect of structurally diverse BET inhibitors on SIRT1 levels is divergent, and the responses might also be cell type-dependent. These findings are important for all SIRT1 and BET inhibitor-related research, and they show that different BET inhibitors might have important individual effects.
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Affiliation(s)
- Jonna Tenhunen
- School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland
| | - Tarja Kokkola
- Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland
| | - Marjo Huovinen
- School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland
| | - Minna Rahnasto-Rilla
- School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland
| | - Maija Lahtela-Kakkonen
- School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland.
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miR-106b-5p promotes cell proliferation and cell cycle progression by directly targeting CDKN1A in osteosarcoma. Exp Ther Med 2020; 19:3203-3210. [PMID: 32266016 PMCID: PMC7132225 DOI: 10.3892/etm.2020.8574] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 10/09/2019] [Indexed: 12/12/2022] Open
Abstract
MicroRNA (miR)-106b-5p has been reported to act as both an oncogene and tumor suppressor in several tumors. The aim of the present study was to investigate the biological function of miR-106b-5p in osteosarcoma (OS). miR-106b-5p expression was observed to be significantly increased in OS tissues and cell lines. MTT assay and flow cytometry analysis determined that miR-106b-5p inhibitor transfection suppressed OS cell proliferation and induced cell cycle G0/G1 phase arrest. Furthermore, bioinformatics analysis and a luciferase reporter assay demonstrated that cyclin-dependent kinase inhibitor 1A (CDKN1A) was a potential target of miR-106b-5p. p21 protein expression was found to be significantly increased by miR-106b-5p downregulation in OS cells. Further analysis demonstrated that CDKN1A was downregulated in OS tissues and was negatively correlated with miR-106b-5p expression. Furthermore, upregulation of CDKN1A expression mimicked, whilst CDKN1A knockdown reversed the suppressive effects of miR-106b-5p inhibitor on OS cell proliferation and cell cycle progression. In summary, the present data suggested that miR-106b-5p promotes cell proliferation and cell cycle progression by directly targeting CDKN1A in OS.
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48
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Hong J, Li S, Markova DZ, Liang A, Kepler CK, Huang Y, Zhou J, Yan J, Chen W, Huang D, Xu K, Ye W. Bromodomain-containing protein 4 inhibition alleviates matrix degradation by enhancing autophagy and suppressing NLRP3 inflammasome activity in NP cells. J Cell Physiol 2020; 235:5736-5749. [PMID: 31975410 DOI: 10.1002/jcp.29508] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 01/09/2020] [Indexed: 02/06/2023]
Abstract
An imbalance between matrix synthesis and degradation is the hallmark of intervertebral disc degeneration while inflammatory cytokines contribute to the imbalance. Bromodomain and extra-terminal domain (BET) family is associated with the pathogenesis of inflammation, and inhibition of BRD4, a vital member of BET family, plays an anti-inflammatory role in many diseases. However, it remains elusive whether BRD4 plays a similar role in nucleus pulposus (NP) cells and participates in the pathogenesis of intervertebral disc degeneration. The present study aims to observe whether BRD4 inhibition regulates matrix metabolism by controlling autophagy and NLRP3 inflammasome activity. Besides, the relationship was investigated among nuclear factor κB (NF-κB) signaling, autophagy and NLRP3 inflammasome in NP cells. Here, real-time polymerase chain reaction, western blot analysis and adenoviral GFP-LC3 vector transduction in vitro were used, and it was revealed that BRD4 inhibition alleviated the matrix degradation and increased autophagy in the presence or absence of tumor necrosis factor α. Moreover, p65 knockdown or treatment with JQ1 and Bay11-7082 demonstrated that BRD4 inhibition attenuated NLRP3 inflammasome activity through NF-κB signaling, while autophagy inhibition by bafilomycin A1 promoted matrix degradation and NLRP3 inflammasome activity in NP cells. In addition, analysis of BRD4 messenger RNA expression in human NP tissues further verified the destructive function of BRD4. Simply, BRD4 inhibition alleviates matrix degradation by enhancing autophagy and suppressing NLRP3 inflammasome activity through NF-κB signaling in NP cells.
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Affiliation(s)
- Junmin Hong
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.,Department of Spine Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shuangxing Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.,Department of Spine Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Dessislava Z Markova
- Department of Orthopedic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Anjing Liang
- Department of Spine Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Christopher K Kepler
- Department of Orthopedic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Yingjie Huang
- Department of Spine Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Department of Orthopedics, The fifth affiliated hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jie Zhou
- Department of Breast Cancer Surgery, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jiansen Yan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.,Department of Spine Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Weijian Chen
- Department of Orthopedics, The fifth affiliated hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Dongsheng Huang
- Department of Spine Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Kang Xu
- Department of Spine Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Experimental Center, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wei Ye
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.,Department of Spine Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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49
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Xu Y, Song S, Wang Z, Ajani JA. The role of hedgehog signaling in gastric cancer: molecular mechanisms, clinical potential, and perspective. Cell Commun Signal 2019; 17:157. [PMID: 31775795 PMCID: PMC6882007 DOI: 10.1186/s12964-019-0479-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 11/11/2019] [Indexed: 02/07/2023] Open
Abstract
Patients with advanced gastric cancer usually have a poor prognosis and limited therapeutic options. Overcoming this challenge requires novel targets and effective drugs. The Hedgehog (Hh) signaling pathway plays a crucial role in the development of the gastrointestinal tract and maintenance of the physiologic function of the stomach. Aberrantly activated Hh signaling is implicated in carcinogenesis as well as maintenance of cancer stem cells. Somatic mutations in the components of Hh signaling (PTCH1 and SMO) have been shown to be a major cause of basal cell carcinoma, and dozens of Hh inhibitors have been developed. To date, two inhibitors (GDC-0449 and LDE225) have been approved by the U.S. Food and Drug Administration to treat basal cell carcinoma and medulloblastoma. Here, we review the role of the Hh signaling in the carcinogenesis and progression of gastric cancer and summarize recent findings on Hh inhibitors in gastric cancer. Hedgehog signaling is often aberrantly activated and plays an important role during inflammation and carcinogenesis of gastric epithelial cells. Further study of the precise mechanisms of Hh signaling in this disease is needed for the validation of therapeutic targets and evaluation of the clinical utility of Hh inhibitors for gastric cancer.
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Affiliation(s)
- Yan Xu
- Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA.,Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, People's Republic of China
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA.
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, People's Republic of China.
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA.
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50
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Zhang W, Ge H, Jiang Y, Huang R, Wu Y, Wang D, Guo S, Li S, Wang Y, Jiang H, Cheng J. Combinational therapeutic targeting of BRD4 and CDK7 synergistically induces anticancer effects in head and neck squamous cell carcinoma. Cancer Lett 2019; 469:510-523. [PMID: 31765738 DOI: 10.1016/j.canlet.2019.11.027] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 10/15/2019] [Accepted: 11/18/2019] [Indexed: 12/27/2022]
Abstract
The bromodomain and extra-terminal domain protein BRD4 has been recognized as a key oncogenic driver and a druggable target against cancer. However, these BRD4 inhibitors as monotherapy were moderate in efficacy in preclinical models. Here we utilized a small-scale drug synergy screen that combined the BRD4 inhibitor (JQ1) with 8 epigenetic or transcriptional targeted chemicals and identified THZ1 (a CDK7 inhibitor) acting synergistically with JQ1 against head neck squamous cell carcinoma (HNSCC). Combinational JQ1 and THZ1 treatment impaired cell proliferation, induced apoptosis and senescence, which were largely recapitulated by dual BRD4 and CDK7 knockdown. Combinational treatment inhibited tumor growth and progression in 4NQO-induced HNSCC and xenograft animal models. RNA-sequencing analyses identified hundreds of differentially expressed genes modulated by JQ1 and THZ1, which were significantly enriched in categories including cell cycle and apoptosis. Mechanistically, combinational treatment reduced H3K27ac enrichment in the super-enhancer region of YAP1, which inactivated its transcription and in turn induced anti-proliferative and pro-apoptotic effects. Combined BRD4 and CDK7 upregulation associated with worst prognosis in HNSCC patients. Collectively, our findings reveal a novel therapeutic strategy of pharmacological inhibitions of BRD4 and CDK7 against HNSCC.
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Affiliation(s)
- Wei Zhang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu, 210029, People's Republic of China; Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Han Ge
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu, 210029, People's Republic of China; Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Yue Jiang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu, 210029, People's Republic of China
| | - Rong Huang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu, 210029, People's Republic of China
| | - Yaping Wu
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu, 210029, People's Republic of China
| | - Dongmiao Wang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu, 210029, People's Republic of China
| | - Songsong Guo
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Sheng Li
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Yanling Wang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu, 210029, People's Republic of China
| | - Hongbing Jiang
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Jie Cheng
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu, 210029, People's Republic of China; Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, 210029, People's Republic of China.
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