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Chi S, Wei F, Li Y, Yu L, Ma C, Fang Y, Yang B, Chen Y, Ding J. BET inhibitor and CDK4/6 inhibitor synergistically inhibit breast cancer by suppressing BRD4 stability and DNA damage repair. Transl Oncol 2025; 51:102212. [PMID: 39591896 PMCID: PMC11629338 DOI: 10.1016/j.tranon.2024.102212] [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: 07/12/2024] [Revised: 11/15/2024] [Accepted: 11/20/2024] [Indexed: 11/28/2024] Open
Abstract
CDK4/6 inhibitors have shown clinical benefits in hormone receptor positive breast cancer. However, monotonous indications and unclear resistance mechanisms greatly limit the clinical application of these inhibitors. We attempt to improve the therapeutic effect of CDK4/6 inhibitors against breast cancer by combination with BET inhibitors. Although this combination therapy has begun to be studied in recent clinical trials, the mechanism of action is not clear. We provide the evidence that CDK4/6 inhibitor LY2835219 plus BRD4 inhibitor OTX-015 synergistically inhibits both ER positive and triple-negative breast cancer cells growth in vitro and in vivo. Mechanistically, LY2835219 accelerates the degradation of BRD4 through the proteasome pathway via inhibition of CDK4 activity. This instability of BRD4 protein in turn enhances the anti-tumor effect of CDK4/6 inhibitor by suppressing transcription of DNA damage repair gene RAD51, and synergistically promotes γ-H2AX accumulation and DNA double-strand breaks. Overall, we demonstrated the potential combined therapeutic value of CDK4/6 and BRD4 inhibitors and elucidated the mechanisms, which may provide a new rational approach for breast cancer patients.
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Affiliation(s)
- Shuaishuai Chi
- Department of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, Zhejiang 0310058, China; State Key Laboratory of Chemical Biology, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, Shanghai 201203, China
| | - Fan Wei
- State Key Laboratory of Chemical Biology, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, Shanghai 201203, China.
| | - Yangsha Li
- State Key Laboratory of Chemical Biology, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Lei Yu
- State Key Laboratory of Chemical Biology, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Chuyao Ma
- State Key Laboratory of Chemical Biology, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Yanfen Fang
- State Key Laboratory of Chemical Biology, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China
| | - Biyu Yang
- State Key Laboratory of Chemical Biology, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, Shanghai 201203, China
| | - Yi Chen
- State Key Laboratory of Chemical Biology, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
| | - Jian Ding
- Department of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, Zhejiang 0310058, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
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Bollmann LM, Lange F, Hamacher A, Biermann L, Schäker-Hübner L, Hansen FK, Kassack MU. Triple Combination of Entinostat, a Bromodomain Inhibitor, and Cisplatin Is a Promising Treatment Option for Bladder Cancer. Cancers (Basel) 2024; 16:3374. [PMID: 39409994 PMCID: PMC11476342 DOI: 10.3390/cancers16193374] [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: 08/30/2024] [Revised: 09/16/2024] [Accepted: 09/30/2024] [Indexed: 10/20/2024] Open
Abstract
BACKGROUND/OBJECTIVES Cisplatin is part of the first-line treatment of advanced urothelial carcinoma. Cisplatin resistance is a major problem but may be overcome by combination treatments such as targeting epigenetic aberrances. Here, we investigated the effect of the class I HDACi entinostat and bromodomain inhibitors (BETis) on the potency of cisplatin in two pairs of sensitive and cisplatin-resistant bladder cancer cell lines. Cisplatin-resistant J82cisR and T24 LTT were 3.8- and 24-fold more resistant to cisplatin compared to the native cell lines J82 and T24. In addition, a hybrid compound (compound 20) comprising structural features of an HDACi and a BETi was investigated. RESULTS We found complete (J82cisR) or partial (T24 LTT) reversal of chemoresistance upon combination of entinostat, JQ1, and cisplatin. The same was found for the BETis JQ35 and OTX015, both in clinical trials, and for compound 20. The combinations were highly synergistic (Chou Talalay analysis) and increased caspase-mediated apoptosis accompanied by enhanced expression of p21, Bim, and FOXO1. Notably, the combinations were at least 4-fold less toxic in non-cancer cell lines HBLAK and HEK293. CONCLUSIONS The triple combination of entinostat, a BETi, and cisplatin is highly synergistic, reverses cisplatin resistance, and may thus serve as a novel therapeutic approach for bladder cancer.
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Affiliation(s)
- Lukas M. Bollmann
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany; (L.M.B.)
| | - Friedrich Lange
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany; (L.M.B.)
| | - Alexandra Hamacher
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany; (L.M.B.)
| | - Lukas Biermann
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany; (L.M.B.)
| | - Linda Schäker-Hübner
- Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany (F.K.H.)
| | - Finn K. Hansen
- Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany (F.K.H.)
| | - Matthias U. Kassack
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany; (L.M.B.)
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Liu N, Wang S, Li M, Zhao N, Wang D, Zhang R, Yu M, Zhao L, Zhang S, Han F, Zhao Y, Liu Q. BET degrader exhibits lower antiproliferative activity than its inhibitor via EGR1 recruiting septins to promote E2F1-3 transcription in triple-negative breast cancer. Pharmacol Res 2024; 208:107377. [PMID: 39209080 DOI: 10.1016/j.phrs.2024.107377] [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: 03/18/2024] [Revised: 08/14/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Abstract
The bromodomain and extraterminal domain (BET) family proteins serve as primary readers of acetylated lysine residues and play crucial roles in cell proliferation and differentiation. Dysregulation of BET proteins has been implicated in tumorigenesis, making them important therapeutic targets. BET-bromodomain (BD) inhibitors and BET-targeting degraders have been developed to inhibit BET proteins. In this study, we found that the BET inhibitor MS645 exhibited superior antiproliferative activity than BET degraders including ARV771, AT1, MZ1 and dBET1 in triple-negative breast cancer (TNBC) cells. Treatment with MS645 led to the dissociation of BETs, MED1 and RNA polymerase II from the E2F1-3 promoter, resulting in the suppression of E2F1-3 transcription and subsequent inhibition of cell growth in TNBC. In contrast, while ARV771 displaced BET proteins from chromatin, it did not significantly alter E2F1-3 expression. Mechanistically, ARV771 induced BRD4 depletion at protein level, which markedly increased EGR1 expression. This elevation of EGR1 subsequently recruited septin 2 and septin 9 to E2F1-3 promoters, enhancing E2F1-3 transcription and promoting cell proliferation rate in vitro and in vivo. Our findings provide valuable insights into differential mechanisms of BET inhibition and highlight potential of developing BET-targeting molecules as therapeutic strategies for TNBC.
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Affiliation(s)
- Nan Liu
- Department of Infectious Diseases and Center of Infectious Diseases and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130061, China.
| | - Shuai Wang
- Bethune Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China
| | - Munan Li
- Bethune Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China
| | - Nan Zhao
- Bethune Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China
| | - Deyu Wang
- Bethune Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China
| | - Rui Zhang
- Bethune Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China
| | - Mingxin Yu
- Department of Infectious Diseases and Center of Infectious Diseases and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130061, China
| | - Luoyi Zhao
- Department of Infectious Diseases and Center of Infectious Diseases and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130061, China
| | - Siwei Zhang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130000, China
| | - Fangbin Han
- Bethune Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China.
| | - Ying Zhao
- Bethune Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China.
| | - Quan Liu
- Department of Infectious Diseases and Center of Infectious Diseases and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130061, China.
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Rao A, Stosic MS, Mohanty C, Suresh D, Wang AR, Lee DL, Nickel KP, Chandrashekar DS, Kimple RJ, Lambert PF, Kendziorski C, Rounge TB, Iyer G. Targeted inhibition of BET proteins in HPV16-positive head and neck squamous cell carcinoma reveals heterogeneous transcriptional responses. Front Oncol 2024; 14:1440836. [PMID: 39301555 PMCID: PMC11410754 DOI: 10.3389/fonc.2024.1440836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/21/2024] [Indexed: 09/22/2024] Open
Abstract
Human papillomaviruses (HPV), most commonly HPV16, are associated with a subset of head and neck squamous cell carcinoma (HNSCC) tumors, primarily oropharyngeal carcinomas, with integration of viral genomes into host chromosomes associated with worse survival outcomes. We analyzed TCGA data and found that HPV+ HNSCC expressed higher transcript levels of the bromodomain and extra terminal domain (BET) family of transcriptional coregulators. The role of BET protein-mediated transcription of viral-cellular genes in the viral-HNSCC genomes needs to be better understood. Using a combination of TAME-Seq, qRT-PCR, and immunoblot analyses, we show that BET inhibition downregulates E6 and E7 significantly, with heterogeneity in the downregulation of viral transcription across different HPV+ HNSCC cell lines. Chemical BET inhibition was phenocopied with the knockdown of BRD4, mirroring the downregulation of viral E6 and E7 expression. We found that BET inhibition directly downregulated c-Myc and E2F expression and induced CDKN1A (p21) expression, leading to a G1-cell cycle arrest with apoptotic activity. Overall, our studies demonstrate that BET inhibition regulates both E6 and E7 viral and key cellular cell cycle regulator E2F gene expression and cellular gene expression in HPV-associated HNSCC and highlight the potential of BET inhibitors as a therapeutic strategy for this disease while also underscoring the importance of considering the heterogeneity in cellular responses to BET inhibition.
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Affiliation(s)
- Aakarsha Rao
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
| | - Milan S. Stosic
- Department of Life Sciences and Health, Faculty of Health Sciences, OsloMet - Oslo Metropolitan University, Oslo, Norway
- Department of Microbiology and Infection Control, Akershus University Hospital, Lørenskog, Norway
| | - Chitrasen Mohanty
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, United States
| | - Dhruthi Suresh
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
| | - Albert R. Wang
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, United States
| | - Denis L. Lee
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
- University of Wisconsin Carbone Cancer Center, Madison, WI, United States
| | - Kwangok P. Nickel
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
- University of Wisconsin Carbone Cancer Center, Madison, WI, United States
| | - Darshan S. Chandrashekar
- Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Randall J. Kimple
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
- University of Wisconsin Carbone Cancer Center, Madison, WI, United States
| | - Paul F. Lambert
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
- University of Wisconsin Carbone Cancer Center, Madison, WI, United States
| | - Christina Kendziorski
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, United States
| | - Trine B. Rounge
- Centre for Bioinformatics, Department of Pharmacy, University of Oslo, Oslo, Norway
- Norwegian Institute of Public Health, Cancer Registry of Norway, Oslo, Norway
| | - Gopal Iyer
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
- University of Wisconsin Carbone Cancer Center, Madison, WI, United States
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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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Lind J, Aksoy O, Prchal-Murphy M, Fan F, Fulciniti M, Stoiber D, Bakiri L, Wagner EF, Zwickl-Traxler E, Sattler M, Kollmann K, Vallet S, Podar K. Dual therapeutic targeting of MYC and JUNB transcriptional programs for enhanced anti-myeloma activity. Blood Cancer J 2024; 14:138. [PMID: 39160158 PMCID: PMC11333473 DOI: 10.1038/s41408-024-01117-4] [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: 04/13/2024] [Revised: 07/25/2024] [Accepted: 07/29/2024] [Indexed: 08/21/2024] Open
Abstract
Deregulation of transcription factors (TFs) leading to uncontrolled proliferation of tumor cells within the microenvironment represents a hallmark of cancer. However, the biological and clinical impact of transcriptional interference, particularly in multiple myeloma (MM) cells, remains poorly understood. The present study shows for the first time that MYC and JUNB, two crucial TFs implicated in MM pathogenesis, orchestrate distinct transcriptional programs. Specifically, our data revealed that expression levels of MYC, JUNB, and their respective downstream targets do not correlate and that their global chromatin-binding patterns are not significantly overlapping. Mechanistically, MYC expression was not affected by JUNB knockdown, and conversely, JUNB expression and transcriptional activity were not affected by MYC knockdown. Moreover, suppression of MYC levels in MM cells via targeting the master regulator BRD4 by either siRNA-mediated knockdown or treatment with the novel proteolysis targeting chimera (PROTAC) MZ-1 overcame bone marrow (BM) stroma cell/IL-6-induced MYC- but not MEK-dependent JUNB-upregulation and transcriptional activity. Consequently, targeting of the two non-overlapping MYC- and JUNB-transcriptoms by MZ-1 in combination with genetic or pharmacological JUNB-targeting approaches synergistically enhanced MM cell death, both in 2D and our novel dynamic 3D models of the BM milieu as well as in murine xenografts. In summary, our data emphasize the opportunity to employ MYC and JUNB dual-targeting treatment strategies in MM as another exciting approach to further improve patient outcomes.
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Affiliation(s)
- Judith Lind
- Division of Molecular Oncology and Hematology, Department of Basic and Translational Oncology, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria
| | - Osman Aksoy
- Division of Molecular Oncology and Hematology, Department of Basic and Translational Oncology, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria
| | - Michaela Prchal-Murphy
- Pharmacology and Toxicology, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine, Vienna, Austria
| | - Fengjuan Fan
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mariateresa Fulciniti
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Dagmar Stoiber
- Division of Pharmacology, Department of Pharmacology, Physiology and Microbiology, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria
| | - Latifa Bakiri
- Genes & Disease Group, Department of Laboratory Medicine, Medical University of Vienna (MUW), Vienna, Austria
| | - Erwin F Wagner
- Genes & Disease Group, Department of Laboratory Medicine, Medical University of Vienna (MUW), Vienna, Austria
- Genes & Disease Group, Department of Dermatology, Medical University of Vienna (MUW), Vienna, Austria
| | | | - Martin Sattler
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Karoline Kollmann
- Pharmacology and Toxicology, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine, Vienna, Austria
| | - Sonia Vallet
- Division of Molecular Oncology and Hematology, Department of Basic and Translational Oncology, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria
- Division of Internal Medicine 2, University Hospital Krems, Krems/ Donau, Austria
| | - Klaus Podar
- Division of Molecular Oncology and Hematology, Department of Basic and Translational Oncology, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria.
- Division of Internal Medicine 2, University Hospital Krems, Krems/ Donau, Austria.
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Wu T, Hou H, Dey A, Bachu M, Chen X, Wisniewski J, Kudoh F, Chen C, Chauhan S, Xiao H, Pan R, Ozato K. Bromodomain protein BRD4 directs mitotic cell division of mouse fibroblasts by inhibiting DNA damage. iScience 2024; 27:109797. [PMID: 38993671 PMCID: PMC11237862 DOI: 10.1016/j.isci.2024.109797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 10/30/2023] [Accepted: 04/18/2024] [Indexed: 07/13/2024] Open
Abstract
Bromodomain protein BRD4 binds to acetylated histones to regulate transcription. BRD4 also drives cancer cell proliferation. However, the role of BRD4 in normal cell growth has remained unclear. Here, we investigated this question by using mouse embryonic fibroblasts with conditional Brd4 knockout (KO). We found that Brd4KO cells grow more slowly than wild type cells; they do not complete replication, fail to achieve mitosis, and exhibit extensive DNA damage throughout all cell cycle stages. BRD4 was required for expression of more than 450 cell cycle genes including genes encoding core histones and centromere/kinetochore proteins that are critical for genome replication and chromosomal segregation. Moreover, we show that many genes controlling R-loop formation and DNA damage response (DDR) require BRD4 for expression. Finally, BRD4 constitutively occupied genes controlling R-loop, DDR and cell cycle progression. In summary, BRD4 epigenetically marks above genes and serves as a master regulator of normal cell growth.
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Affiliation(s)
- Tiyun Wu
- Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Haitong Hou
- Science Center for Future Foods, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Anup Dey
- Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Mahesh Bachu
- Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
- Weill Cornell Medicine, Graduate School of Medical Sciences, 1300 York Avenue Box 65, New York, NY 10065, USA
| | - Xiongfong Chen
- CCR-SF Bioinformatics Group, Advanced Biomedical and Computational Sciences, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Jan Wisniewski
- Confocal Microscopy and Digital Imaging Facility, Experimental Immunology Branch, CCR, NCI NIH Bldg 10 Rm 4A05, Bethesda, MD 20892, USA
| | - Fuki Kudoh
- Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Chao Chen
- Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
- Division of Hematology/Oncology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Sakshi Chauhan
- Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Hua Xiao
- Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Richard Pan
- Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Keiko Ozato
- Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
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Chen X, Huang R, Zhang Z, Song X, Shen J, Wu Q. BET Bromodomain Inhibition Potentiates Ocular Melanoma Therapy by Inducing Cell Cycle Arrest. Invest Ophthalmol Vis Sci 2024; 65:11. [PMID: 38967943 PMCID: PMC11232900 DOI: 10.1167/iovs.65.8.11] [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: 01/14/2024] [Accepted: 03/30/2024] [Indexed: 07/06/2024] Open
Abstract
Purpose Ocular melanoma is a common primary malignant ocular tumor in adults with limited effective treatments. Epigenetic regulation plays an important role in tumor development. The switching/sucrose nonfermentation (SWI/SNF) chromatin remodeling complex and bromodomain and extraterminal domain family proteins are epigenetic regulators involved in several cancers. We aimed to screen a candidate small molecule inhibitor targeting these regulators and investigate its effect and mechanism in ocular melanoma. Methods We observed phenotypes caused by knockdown of the corresponding gene and synergistic effects with BRD inhibitor treatment and SWI/SNF complex knockdown. The effect of JQ-1 on ocular melanoma cell cycle and apoptosis was analyzed with flow cytometry. Via RNA sequencing, we also explored the mechanism of BRD4. Results The best tumor inhibitory effect was observed for the BRD4 inhibitor (JQ-1), although there were no statistically obvious changes in the shBRD4 and shBRD9 groups. Interestingly, the inhibitory effect of JQ-1 was decrease in the shBRD4 group. JQ-1 inhibits the growth of melanoma in various cell lines and in tumor-bearing mice. We found 17 of these 28 common differentially expressed genes were downregulated after MEL270 and MEL290 cells treated with JQ-1. Four of these 17 genes, TP53I11, SH2D5, SEMA5A, and MDGA1, were positively correlated with BRD4. In TCGA database, low expression of TP53I11, SH2D5, SEMA5A, and MDGA1 improved the overall survival rate of patients. Furthermore, the disease-free survival rate was increased in the groups with low expression of TP53I11, SH2D5, and SEMA5A. Conclusions JQ-1 may act downstream of BRD4 and suppress ocular melanoma growth by inducing G1 cell cycle arrest.
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Affiliation(s)
- Xingyu Chen
- Department of Ophthalmology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Rui Huang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Zhe Zhang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Xin Song
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Jianfeng Shen
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Qiang Wu
- Department of Ophthalmology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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Bo Y, Zhang Y, Wei L, Pei X, Zhu B, Zanoli L, Kalantar-Zadeh K, Gao F, Yong Z, Zhang T, Zhao W, Wu J. BRD4 plays an antiaging role in the senescence of renal tubular epithelial cells. Transl Androl Urol 2024; 13:1014-1023. [PMID: 38983468 PMCID: PMC11228682 DOI: 10.21037/tau-24-214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 06/25/2024] [Indexed: 07/11/2024] Open
Abstract
Background Age-related kidney failure is often induced by a decrease in the bioavailability of tubular epithelial cells in elderly chronic kidney disease (CKD) patients. BRD4, an epigenetic regulator and a member of the bromodomain and extraterminal (BET) protein family, acts as a super-enhancer (SE) organizing and regulating genes expression during embryogenesis and cancer development. But the physiological function of BRD4 in normal cells has been less studied. This study aimed to research certain biological roles of BRD4 in the process of normal cell aging and discuss the potential mechanisms. Methods In this study, we investigated the biological functions of BRD4 proteins in the aging of renal tubular cells. At first, we used a D-galactose (D-gal) and BRD4 inhibitor (Abbv-075) to replicate kidney senescence in vivo. D-gal and Abbv-075 were then used to measure the aging-related changes, such as changes in cell cycle, β-galactosidase activity, cell migration, and p16 protein expression in vitro. At last, we knocked down and over-expressed BRD4 to investigate the aging-related physiological phenomena in renal tubular cells. Results In vitro, D-gal treatment induced noticeable aging-related changes such as inducing cell apoptosis and cell cycle arrest, increasing β-galactosidase activity as well as up-regulating p16 protein expression in primary human tubular epithelial cells. In the aging mice model, D-gal significantly induced renal function impairment and attenuated BRD4 protein expression. At the same time, the BRD4 inhibitor (Abbv-075) was able to mimic D-gal-induced cell senescence. In vivo, Abbv-075 also decreased kidney function and up-regulated p21 protein expression. When we knocked down the expression of BRD4, the senescence-associated β-galactosidase (SA-β-gal) activity increased dramatically, cell migration was inhibited, and the proportion of cells in the G0/G1 phase increased. Additionally, the knockdown also promoted the expression of the senescence-related proteins p16. When the renal tubular cells were overexpressed with BRD4, cell aging-related indicators were reversed in the D-gal-induced cell aging model. Conclusions BRD4 appears to have an active role in the aging of renal tubular cells in vivo and in vitro. The findings also suggest that BRD4 inhibitors have potential nephrotoxic effects for oncology treatment. BRD4 may be a potential therapeutic biomarker and drug target for aging-related kidney diseases, which warrants additional studies.
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Affiliation(s)
- Yun Bo
- Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yu Zhang
- Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lu Wei
- Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaohua Pei
- Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Bei Zhu
- Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Luca Zanoli
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Kamyar Kalantar-Zadeh
- Division of Nephrology, Tibor Rubin VA Medical Center, Long Beach, CA, USA
- Division of Nephrology, Hypertension, and Kidney Transplantation, University of California, Irvine, Orange, CA, USA
| | - Fei Gao
- Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhenzhu Yong
- Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tao Zhang
- Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Weihong Zhao
- Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jianqing Wu
- Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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10
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Walker FM, Sobral LM, Danis E, Sanford B, Donthula S, Balakrishnan I, Wang D, Pierce A, Karam SD, Kargar S, Serkova NJ, Foreman NK, Venkataraman S, Dowell R, Vibhakar R, Dahl NA. Rapid P-TEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy. Nat Commun 2024; 15:4616. [PMID: 38816355 PMCID: PMC11139976 DOI: 10.1038/s41467-024-48214-3] [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: 03/03/2023] [Accepted: 04/23/2024] [Indexed: 06/01/2024] Open
Abstract
Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. P-TEFb-mediated pause-release of RNA polymerase II (Pol II) is a conserved regulatory mechanism for synchronous transcriptional induction in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. Using model systems of pediatric high-grade glioma, we show that rapid genome-wide reorganization of active chromatin facilitates P-TEFb-mediated nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of P-TEFb disrupts this chromatin reorganization and blunts transcriptional induction, abrogating key adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival. These studies reveal a central role for P-TEFb underpinning the early adaptive response to radiotherapy, opening avenues for combinatorial treatment in these lethal malignancies.
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Affiliation(s)
- Faye M Walker
- Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Lays Martin Sobral
- Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Etienne Danis
- Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO, USA
- University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, CO, USA
| | - Bridget Sanford
- Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Sahiti Donthula
- Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Ilango Balakrishnan
- Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Dong Wang
- Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Angela Pierce
- Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Sana D Karam
- Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Soudabeh Kargar
- University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, CO, USA
| | - Natalie J Serkova
- Department of Radiology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Nicholas K Foreman
- Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
- Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA
- Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, USA
| | - Sujatha Venkataraman
- Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Robin Dowell
- Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO, USA
- BioFrontiers Institute, University of Colorado, Boulder, CO, USA
| | - Rajeev Vibhakar
- Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
- Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA
- Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, USA
| | - Nathan A Dahl
- Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
- Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA.
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11
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Sotiriadis S, Beil J, Berchtold S, Smirnow I, Schenk A, Lauer UM. Multimodal Therapy Approaches for NUT Carcinoma by Dual Combination of Oncolytic Virus Talimogene Laherparepvec with Small Molecule Inhibitors. Viruses 2024; 16:775. [PMID: 38793657 PMCID: PMC11125747 DOI: 10.3390/v16050775] [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: 04/04/2024] [Revised: 04/23/2024] [Accepted: 05/09/2024] [Indexed: 05/26/2024] Open
Abstract
NUT (nuclear-protein-in-testis) carcinoma (NC) is a highly aggressive tumor disease. Given that current treatment regimens offer a median survival of six months only, it is likely that this type of tumor requires an extended multimodal treatment approach to improve prognosis. In an earlier case report, we could show that an oncolytic herpes simplex virus (T-VEC) is functional in NC patients. To identify further combination partners for T-VEC, we have investigated the anti-tumoral effects of T-VEC and five different small molecule inhibitors (SMIs) alone and in combination in human NC cell lines. Dual combinations were found to result in higher rates of tumor cell reductions when compared to the respective monotherapy as demonstrated by viability assays and real-time tumor cell growth monitoring. Interestingly, we found that the combination of T-VEC with SMIs resulted in both stronger and earlier reductions in the expression of c-Myc, a main driver of NC cell proliferation, when compared to T-VEC monotherapy. These results indicate the great potential of combinatorial therapies using oncolytic viruses and SMIs to control the highly aggressive behavior of NC cancers and probably will pave the way for innovative multimodal clinical studies in the near future.
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Affiliation(s)
- Stavros Sotiriadis
- Department of Medical Oncology and Pneumology, Virotherapy Center Tübingen (VCT), Medical University Hospital, 72076 Tübingen, Germany; (S.S.)
| | - Julia Beil
- Department of Medical Oncology and Pneumology, Virotherapy Center Tübingen (VCT), Medical University Hospital, 72076 Tübingen, Germany; (S.S.)
- German Cancer Consortium (DKTK), Partner Site Tübingen, a Partnership between DKFZ and University Hospital Tübingen, 72076 Tübingen, Germany
| | - Susanne Berchtold
- Department of Medical Oncology and Pneumology, Virotherapy Center Tübingen (VCT), Medical University Hospital, 72076 Tübingen, Germany; (S.S.)
| | - Irina Smirnow
- Department of Medical Oncology and Pneumology, Virotherapy Center Tübingen (VCT), Medical University Hospital, 72076 Tübingen, Germany; (S.S.)
| | - Andrea Schenk
- Department of Medical Oncology and Pneumology, Virotherapy Center Tübingen (VCT), Medical University Hospital, 72076 Tübingen, Germany; (S.S.)
| | - Ulrich M. Lauer
- Department of Medical Oncology and Pneumology, Virotherapy Center Tübingen (VCT), Medical University Hospital, 72076 Tübingen, Germany; (S.S.)
- German Cancer Consortium (DKTK), Partner Site Tübingen, a Partnership between DKFZ and University Hospital Tübingen, 72076 Tübingen, Germany
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12
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Mao S, Song C, Huang H, Nie Y, Ding K, Cui J, Tian J, Tang H. Role of transcriptional cofactors in cardiovascular diseases. Biochem Biophys Res Commun 2024; 706:149757. [PMID: 38490050 DOI: 10.1016/j.bbrc.2024.149757] [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: 12/09/2023] [Revised: 02/16/2024] [Accepted: 03/04/2024] [Indexed: 03/17/2024]
Abstract
Cardiovascular disease is a main cause of mortality in the world and the highest incidence of all diseases. However, the mechanism of the pathogenesis of cardiovascular disease is still unclear, and we need to continue to explore its mechanism of action. The occurrence and development of cardiovascular disease is significantly associated with genetic abnormalities, and gene expression is affected by transcriptional regulation. In this complex process, the protein-protein interaction promotes the RNA polymerase II to the initiation site. And in this process of transcriptional regulation, transcriptional cofactors are responsible for passing cues from enhancers to promoters and promoting the binding of RNA polymerases to promoters, so transcription cofactors playing a key role in gene expression regulation. There is growing evidence that transcriptional cofactors play a critical role in cardiovascular disease. Transcriptional cofactors can promote or inhibit transcription by affecting the function of transcription factors. It can affect the initiation and elongation process of transcription by forming complexes with transcription factors, which are important for the stabilization of DNA rings. It can also act as a protein that interacts with other proteins to affect the expression of other genes. Therefore, the aim of this overview is to summarize the effect of some transcriptional cofactors such as BRD4, EP300, MED1, EZH2, YAP, SIRT6 in cardiovascular disease and to provide a promising therapeutic strategy for the treatment of cardiovascular disease.
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Affiliation(s)
- Shuqing Mao
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Chao Song
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Hong Huang
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Yali Nie
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Kai Ding
- The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Jian Cui
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China; Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Jinwei Tian
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
| | - Huifang Tang
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
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13
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Morino S, Mashima T, Shirai F, Nagayama S, Katayama R, Seimiya H. BET protein-dependent E2F pathway activity confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer. Cancer Lett 2024; 584:216632. [PMID: 38216082 DOI: 10.1016/j.canlet.2024.216632] [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: 09/27/2023] [Revised: 12/27/2023] [Accepted: 01/09/2024] [Indexed: 01/14/2024]
Abstract
WNT/β-catenin signaling is aberrantly activated in colorectal cancer (CRC) mainly by loss-of-function mutations in adenomatous polyposis coli (APC) and is involved in tumor progression. Tankyrase inhibitors, which suppress WNT/β-catenin signaling, are currently in pre-clinical and clinical trials. However, the mechanisms of resistance to tankyrase inhibitors remain unclear. In this study, we established tankyrase inhibitor-resistant CRC cells, JC73-RK100, from APC-mutated patient-derived CRC cells. JC73-RK100 cells and several CRC cell lines were sensitive to tankyrase inhibitors at low concentrations but were resistant at high concentrations, showing an intrinsic/acquired bell-shaped dose response. Mechanistically, tankyrase inhibitors at high concentrations promoted BRD3/4-dependent E2F target gene transcription and over-activated cell cycle progression in these cells. BET inhibitors canceled the bell-shaped dose response to tankyrase inhibitors. Combination of tankyrase and BET inhibitors significantly suppressed tumor growth in a mouse xenograft model. These observations suggest that the combination of tankyrase and BET inhibitors may be a useful therapeutic approach to overcome the resistance of a subset of CRCs to tankyrase inhibitors.
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Affiliation(s)
- Shun Morino
- Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
| | - Tetsuo Mashima
- Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Fumiyuki Shirai
- Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan
| | - Satoshi Nagayama
- Department of Colorectal Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan; Department of Surgery, Uji-Tokushukai Medical Center, Kyoto, Japan
| | - Ryohei Katayama
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan; Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiroyuki Seimiya
- Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
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14
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Ali I, Cha HJ, Lim B, Chae CH, Youm J, Park WJ, Lee SH, Kim JH, Jeong D, Lim JK, Hwang YH, Roe JS, Woo JS, Lee K, Choi G. DW71177: A novel [1,2,4]triazolo[4,3-a]quinoxaline-based potent and BD1-Selective BET inhibitor for the treatment of acute myeloid leukemia. Eur J Med Chem 2024; 265:116052. [PMID: 38134745 DOI: 10.1016/j.ejmech.2023.116052] [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: 10/10/2023] [Revised: 11/26/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023]
Abstract
The bromodomain and extraterminal domain (BET) family proteins recognize acetyl-lysine (Kac) at the histone tail through two tandem bromodomains, i.e., BD1 and BD2, to regulate gene expression. BET proteins are attractive therapeutic targets in cancer due to their involvement in oncogenic transcriptional activation, and bromodomains have defined Kac-binding pockets. Here, we present DW-71177, a potent BET inhibitor that selectively interacts with BD1 and exhibits strong antileukemic activity. X-ray crystallography, isothermal titration calorimetry, and molecular dynamic studies have revealed the robust and specific binding of DW-71177 to the Kac-binding pocket of BD1. DW-71177 effectively inhibits oncogenes comparable to the pan-BET inhibitor OTX-015, but with a milder impact on housekeeping genes. It efficiently blocks cancer-associated transcriptional changes by targeting genes that are highly enriched with BRD4 and histone acetylation marks, suggesting that BD1-selective targeting could be an effective and safe therapeutic strategy against leukemia.
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Affiliation(s)
- Imran Ali
- Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, Korea National University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 34113, Republic of Korea
| | - Hyung Jin Cha
- Department of Life Sciences, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Byungho Lim
- Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Chong Hak Chae
- Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Jihyun Youm
- Dongwha Pharm Research Institute, 71 Tapsil-ro, 35 Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 17084, Republic of Korea
| | - Whui Jung Park
- Dongwha Pharm Research Institute, 71 Tapsil-ro, 35 Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 17084, Republic of Korea
| | - Sang Ho Lee
- Dongwha Pharm Research Institute, 71 Tapsil-ro, 35 Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 17084, Republic of Korea
| | - Jung Hwan Kim
- Dongwha Pharm Research Institute, 71 Tapsil-ro, 35 Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 17084, Republic of Korea
| | - Docgyun Jeong
- Dongwha Pharm Research Institute, 71 Tapsil-ro, 35 Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 17084, Republic of Korea
| | - Jae Kyung Lim
- Dongwha Pharm Research Institute, 71 Tapsil-ro, 35 Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 17084, Republic of Korea
| | - Yun-Ha Hwang
- Dongwha Pharm Research Institute, 71 Tapsil-ro, 35 Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 17084, Republic of Korea
| | - Jae-Seok Roe
- Department of Biochemistry, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Jae-Sung Woo
- Department of Life Sciences, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
| | - Kwangho Lee
- Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, Korea National University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 34113, Republic of Korea.
| | - Gildon Choi
- Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, Korea National University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 34113, Republic of Korea.
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15
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Shirbhate E, Singh V, Jahoriya V, Mishra A, Veerasamy R, Tiwari AK, Rajak H. Dual inhibitors of HDAC and other epigenetic regulators: A novel strategy for cancer treatment. Eur J Med Chem 2024; 263:115938. [PMID: 37989059 DOI: 10.1016/j.ejmech.2023.115938] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 10/25/2023] [Accepted: 11/05/2023] [Indexed: 11/23/2023]
Abstract
A significant advancement in the field of epigenetic drug discovery has been evidenced in recent years. Epigenetic alterations are hereditary, nevertheless reversible variations to DNA or histone adaptations that regulate gene function individualistically of the fundamental sequence. The design and synthesis of various drugs targeting epigenetic regulators open a new door for epigenetic-targeted therapies to parade worthwhile therapeutic potential for haematological and solid malignancies. Several ongoing clinical trials on dual targeting strategy are being conducted comprising HDAC inhibitory component and an epigenetic regulating agent. In this perspective, the review discusses the pharmacological aspects of HDAC and other epigenetic regulating factors as dual inhibitors as an emerging alternative approach for combination therapies.
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Affiliation(s)
- Ekta Shirbhate
- Department of Pharmacy, Guru Ghasidas University, Bilaspur, 495 009, CG, India
| | - Vaibhav Singh
- Department of Pharmacy, Guru Ghasidas University, Bilaspur, 495 009, CG, India
| | - Varsha Jahoriya
- Department of Pharmacy, Guru Ghasidas University, Bilaspur, 495 009, CG, India
| | - Aditya Mishra
- Department of Pharmacy, Guru Ghasidas University, Bilaspur, 495 009, CG, India
| | - Ravichandran Veerasamy
- Faculty of Pharmacy, AIMST University, Semeling, 08100, Bedong, Kedah Darul Aman, Malaysia
| | - Amit K Tiwari
- Cancer & System Therapeutics, UAMS College of Pharmacy, UAMS - University of Arkansas for Medical Sciences, AR, United States
| | - Harish Rajak
- Department of Pharmacy, Guru Ghasidas University, Bilaspur, 495 009, CG, India.
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16
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Jiang S, Zhang JX, Shen WL, Lu Y, Zhou SL, Dong XM, Liao MJ, Bi ZF, Hu Q, Yao W, Zhang MQ, Gao SJ, Xiao SH. Genome-wide identification of GTE family proteins in sugarcane (Saccharum spontaneum) reveals that SsGTEL3a confers drought tolerance. PLANT PHYSIOLOGY AND BIOCHEMISTRY : PPB 2023; 205:108169. [PMID: 37977028 DOI: 10.1016/j.plaphy.2023.108169] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/29/2023] [Accepted: 11/06/2023] [Indexed: 11/19/2023]
Abstract
The bromodomain is a highly conserved protein domain that specifically binds to acetylated lysine residues in histones, thereby activating transcription of target genes. Although some progress in Global Transcription Factor Group E (GTE) has been achieved in numerous animals and a few plant species, no systematic analysis of GTE gene families has been reported yet in sugarcane. In our study, 37 GTE and GTE-Like (GTEL) genes were characterized in the Saccharum spontaneum. All SsGTE/SsGTEL members were heterogeneously located on all chromosomes of the sugarcane genome and divided into five groups. Transcriptome data showed that SsGTEL3a was expressed at significantly higher levels under drought stress in drought-resistant varieties than in drought-sensitive varieties. Moreover, the overexpression of SsGTEL3a significantly improved the drought tolerance in Arabidopsis through improving the scavenging ability of reactive oxygen species. Additionally, an interaction between ScFAR1 and SsGTEL3a was identified, with ScFAR1 showing a positive response to drought stress in bacterium. In summary, this systematic analysis of GTE gene family in sugarcane and functional research of SsGTEL3a broadened deeper insight into their evolutionary dynamics and functional properties and provided new candidate genes for drought-resistant molecular breeding of sugarcane.
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Affiliation(s)
- Shuo Jiang
- State Key Lab for Conservation and Utilization of Subtropical Agri-Biological Resources, Guangxi Key Lab for Sugarcane Biology, College of Agriculture, Guangxi University, Nanning, 530004, China
| | - Jin-Xu Zhang
- State Key Lab for Conservation and Utilization of Subtropical Agri-Biological Resources, Guangxi Key Lab for Sugarcane Biology, College of Agriculture, Guangxi University, Nanning, 530004, China
| | - Wen-Long Shen
- State Key Lab for Conservation and Utilization of Subtropical Agri-Biological Resources, Guangxi Key Lab for Sugarcane Biology, College of Agriculture, Guangxi University, Nanning, 530004, China
| | - Yan Lu
- State Key Lab for Conservation and Utilization of Subtropical Agri-Biological Resources, Guangxi Key Lab for Sugarcane Biology, College of Agriculture, Guangxi University, Nanning, 530004, China
| | - Shao-Li Zhou
- State Key Lab for Conservation and Utilization of Subtropical Agri-Biological Resources, Guangxi Key Lab for Sugarcane Biology, College of Agriculture, Guangxi University, Nanning, 530004, China
| | - Xian-Man Dong
- State Key Lab for Conservation and Utilization of Subtropical Agri-Biological Resources, Guangxi Key Lab for Sugarcane Biology, College of Agriculture, Guangxi University, Nanning, 530004, China
| | - Ming-Jing Liao
- State Key Lab for Conservation and Utilization of Subtropical Agri-Biological Resources, Guangxi Key Lab for Sugarcane Biology, College of Agriculture, Guangxi University, Nanning, 530004, China
| | - Zhao-Fu Bi
- State Key Lab for Conservation and Utilization of Subtropical Agri-Biological Resources, Guangxi Key Lab for Sugarcane Biology, College of Agriculture, Guangxi University, Nanning, 530004, China
| | - Qin Hu
- State Key Lab for Conservation and Utilization of Subtropical Agri-Biological Resources, Guangxi Key Lab for Sugarcane Biology, College of Agriculture, Guangxi University, Nanning, 530004, China
| | - Wei Yao
- State Key Lab for Conservation and Utilization of Subtropical Agri-Biological Resources, Guangxi Key Lab for Sugarcane Biology, College of Agriculture, Guangxi University, Nanning, 530004, China
| | - Mu-Qing Zhang
- State Key Lab for Conservation and Utilization of Subtropical Agri-Biological Resources, Guangxi Key Lab for Sugarcane Biology, College of Agriculture, Guangxi University, Nanning, 530004, China
| | - San-Ji Gao
- National Engineering Research Center for Sugarcane, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.
| | - Sheng-Hua Xiao
- State Key Lab for Conservation and Utilization of Subtropical Agri-Biological Resources, Guangxi Key Lab for Sugarcane Biology, College of Agriculture, Guangxi University, Nanning, 530004, China.
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17
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Wang ZQ, Zhang ZC, Wu YY, Pi YN, Lou SH, Liu TB, Lou G, Yang C. Bromodomain and extraterminal (BET) proteins: biological functions, diseases, and targeted therapy. Signal Transduct Target Ther 2023; 8:420. [PMID: 37926722 PMCID: PMC10625992 DOI: 10.1038/s41392-023-01647-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 08/23/2023] [Accepted: 09/12/2023] [Indexed: 11/07/2023] Open
Abstract
BET proteins, which influence gene expression and contribute to the development of cancer, are epigenetic interpreters. Thus, BET inhibitors represent a novel form of epigenetic anticancer treatment. Although preliminary clinical trials have shown the anticancer potential of BET inhibitors, it appears that these drugs have limited effectiveness when used alone. Therefore, given the limited monotherapeutic activity of BET inhibitors, their use in combination with other drugs warrants attention, including the meaningful variations in pharmacodynamic activity among chosen drug combinations. In this paper, we review the function of BET proteins, the preclinical justification for BET protein targeting in cancer, recent advances in small-molecule BET inhibitors, and preliminary clinical trial findings. We elucidate BET inhibitor resistance mechanisms, shed light on the associated adverse events, investigate the potential of combining these inhibitors with diverse therapeutic agents, present a comprehensive compilation of synergistic treatments involving BET inhibitors, and provide an outlook on their future prospects as potent antitumor agents. We conclude by suggesting that combining BET inhibitors with other anticancer drugs and innovative next-generation agents holds great potential for advancing the effective targeting of BET proteins as a promising anticancer strategy.
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Affiliation(s)
- Zhi-Qiang Wang
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Zhao-Cong Zhang
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Yu-Yang Wu
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Ya-Nan Pi
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Sheng-Han Lou
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Tian-Bo Liu
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, 150086, China
| | - Ge Lou
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, 150086, China.
| | - Chang Yang
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin, 150086, China.
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18
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Wahi A, Manchanda N, Jain P, Jadhav HR. Targeting the epigenetic reader "BET" as a therapeutic strategy for cancer. Bioorg Chem 2023; 140:106833. [PMID: 37683545 DOI: 10.1016/j.bioorg.2023.106833] [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: 07/04/2023] [Revised: 08/22/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023]
Abstract
Bromodomain and extraterminal (BET) proteins have the ability to bind to acetylated lysine residues present in both histones and non-histone proteins. This binding is facilitated by the presence of tandem bromodomains. The regulatory role of BET proteins extends to chromatin dynamics, cellular processes, and disease progression. The BET family comprises of BRD 2, 3, 4 and BRDT. The BET proteins are a class of epigenetic readers that regulate the transcriptional activity of a multitude of genes that are involved in the pathogenesis of cancer. Thus, targeting BET proteins has been identified as a potentially efficacious approach for the treatment of cancer. BET inhibitors (BETis) are known to interfere with the binding of BET proteins to acetylated lysine residues of chromatin, thereby leading to the suppression of transcription of several genes, including oncogenic transcription factors. Here in this review, we focus on role of Bromodomain and extra C-terminal (BET) proteins in cancer progression. Furthermore, numerous small-molecule inhibitors with pan-BET activity have been documented, with certain compounds currently undergoing clinical assessment. However, it is apparent that the clinical effectiveness of the present BET inhibitors is restricted, prompting the exploration of novel technologies to enhance their clinical outcomes and mitigate undesired adverse effects. Thus, strategies like development of selective BET-BD1, & BD2 inhibitors, dual and acting BET are also presented in this review and attempts to cover the chemistry needed for proper establishment of designed molecules into BRD have been made. Moreover, the review attempts to summarize the details of research till date and proposes a space for future development of BET inhibitor with diminished side effects. It can be concluded that discovery of isoform selective BET inhibitors can be a way forward in order to develop BET inhibitors with negligible side effects.
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Affiliation(s)
- Abhishek Wahi
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, Govt. of NCT of Delhi, Delhi, New Delhi 110017, India
| | - Namish Manchanda
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, Govt. of NCT of Delhi, Delhi, New Delhi 110017, India
| | - Priti Jain
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, Govt. of NCT of Delhi, Delhi, New Delhi 110017, India.
| | - Hemant R Jadhav
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani-Pilani Campus, Vidya Vihar Pilani, Rajasthan 333031, India
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19
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Behrens RT, Rajashekar JK, Bruce JW, Evans EL, Hansen AM, Salazar-Quiroz N, Simons LM, Ahlquist P, Hultquist JF, Kumar P, Sherer NM. Exploiting a rodent cell block for intrinsic resistance to HIV-1 gene expression in human T cells. mBio 2023; 14:e0042023. [PMID: 37676006 PMCID: PMC10653828 DOI: 10.1128/mbio.00420-23] [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: 04/06/2023] [Accepted: 07/13/2023] [Indexed: 09/08/2023] Open
Abstract
IMPORTANCE Unlike humans, mice are unable to support HIV-1 infection. This is due, in part, to a constellation of defined minor, species-specific differences in conserved host proteins needed for viral gene expression. Here, we used precision CRISPR/Cas9 gene editing to engineer a "mousified" version of one such host protein, cyclin T1 (CCNT1), in human T cells. CCNT1 is essential for efficient HIV-1 transcription, making it an intriguing target for gene-based inactivation of virus replication. We show that isogenic cell lines engineered to encode CCNT1 bearing a single mouse-informed amino acid change (tyrosine in place of cysteine at position 261) exhibit potent, durable, and broad-spectrum resistance to HIV-1 and other pathogenic lentiviruses, and with no discernible impact on host cell biology. These results provide proof of concept for targeting CCNT1 in the context of one or more functional HIV-1 cure strategies.
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Affiliation(s)
- Ryan T. Behrens
- McArdle Laboratory for Cancer Research and Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Institute for Molecular Virology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Jyothi Krishnaswamy Rajashekar
- Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, Connecticut, USA
| | - James W. Bruce
- McArdle Laboratory for Cancer Research and Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Institute for Molecular Virology, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Morgridge Institute for Research, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Edward L. Evans
- McArdle Laboratory for Cancer Research and Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Institute for Molecular Virology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Amelia M. Hansen
- McArdle Laboratory for Cancer Research and Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Institute for Molecular Virology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Natalia Salazar-Quiroz
- Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Lacy M. Simons
- Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Paul Ahlquist
- McArdle Laboratory for Cancer Research and Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Institute for Molecular Virology, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Morgridge Institute for Research, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Judd F. Hultquist
- Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Priti Kumar
- Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Nathan M. Sherer
- McArdle Laboratory for Cancer Research and Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Institute for Molecular Virology, University of Wisconsin-Madison, Madison, Wisconsin, USA
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20
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Hamilton G, Stickler S, Rath B. Integration of signaling pathway and bromodomain and extra-terminal domain inhibition for the treatment of mutant Kirsten rat sarcoma viral oncogene homolog cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2023; 4:1027-1038. [PMID: 38023987 PMCID: PMC10651355 DOI: 10.37349/etat.2023.00178] [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: 03/29/2023] [Accepted: 09/04/2023] [Indexed: 12/01/2023] Open
Abstract
Mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) is now a drugable oncogenic driver and the KRAS G12C variant responds clinically to sotorasib and adagrasib that covalently block the cysteine of the active center and inhibit downstream signaling and proliferation. Unfortunately, progression-free survival (PFS) of lung cancer patients is only 5-6 months and no survival advantage has been found for sotorasib in comparison to docetaxel chemotherapy. Increased responses to KRAS inhibitors are tested in combination with the son of sevenless 1 (SOS1) inhibitors, upstream and downstream signaling modulators as well as chemotherapeutics. Some of these approaches are limited by toxicity to normal tissues and by diverse mechanisms of resistance. In essence, most of these attempts are directed to the inhibition of proliferation by impairment of the signal transduction pathways. The final target of KRAS-mediated growth stimulation is MYC in the cell nucleus that stimulates transcription of a host of genes. In detail, MYC alters genomic enhancer and super-enhancers of transcription that are frequently deregulated in cancer. Such enhancers can be targeted by bromodomain and extra-terminal (BET) inhibitors (BETi) or degraders and this review discusses whether integrated SOS1 inhibition and BET targeting of MYC synergizes against mutant KRAS tumor growth. BET degraders in the form of proteolysis-targeting chimeras (PROTACs) combined with BAY-293-mediated SOS1 inhibition revealed marked cytotoxic synergy against mutant KRAS cancer cells and may constitute a promising option for clinical treatment.
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Affiliation(s)
- Gerhard Hamilton
- Department of Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria
| | - Sandra Stickler
- Department of Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria
| | - Barbara Rath
- Department of Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria
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21
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Rao A, Ni Z, Suresh D, Mohanty C, Wang AR, Lee DL, Nickel KP, Varambally SRJ, Lambert PF, Kendziorski C, Iyer G. Targeted inhibition of BET proteins in HPV-16 associated head and neck squamous cell carcinoma reveals heterogeneous transcription response. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.02.560587. [PMID: 37873389 PMCID: PMC10592929 DOI: 10.1101/2023.10.02.560587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Integrated human papillomavirus (HPV-16) associated head and neck squamous cell carcinoma (HNSCC) tumors have worse survival outcomes compared to episomal HPV-16 HNSCC tumors. Therefore, there is a need to differentiate treatment for HPV-16 integrated HNSCC from other viral forms. We analyzed TCGA data and found that HPV+ HNSCC expressed higher transcript levels of the bromodomain and extra terminal domain (BET) family of transcriptional coregulators. However, the mechanism of BET protein-mediated transcription of viral-cellular genes in the integrated viral-HNSCC genomes needs to be better understood. We show that BET inhibition downregulates E6 significantly independent of the viral transcription factor, E2, and there was overall heterogeneity in the downregulation of viral transcription in response to the effects of BET inhibition across HPV-associated cell lines. Chemical BET inhibition was phenocopied with the knockdown of BRD4 and mirrored downregulation of viral E6 and E7 expression. Strikingly, there was heterogeneity in the reactivation of p53 levels despite E6 downregulation, while E7 downregulation did not alter Rb levels significantly. We identified that BET inhibition directly downregulated c-Myc and E2F expression and induced CDKN1A expression. Overall, our studies show that BET inhibition provokes a G1-cell cycle arrest with apoptotic activity and suggests that BET inhibition regulates both viral and cellular gene expression in HPV-associated HNSCC.
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Affiliation(s)
- Aakarsha Rao
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53705, USA
| | - Zijian Ni
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Dhruthi Suresh
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53705, USA
| | - Chitrasen Mohanty
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Albert R. Wang
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53705, USA
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Denis L Lee
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
- University of Wisconsin Carbone Cancer Center, Madison, 53705, WI, USA
| | - Kwangok P. Nickel
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53705, USA
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Sooryanarayana Randall J. Varambally
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53705, USA
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
- Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Paul F. Lambert
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
- University of Wisconsin Carbone Cancer Center, Madison, 53705, WI, USA
| | - Christina Kendziorski
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Gopal Iyer
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53705, USA
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
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22
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Schmitt A, Grimm M, Kreienkamp N, Junge H, Labisch J, Schuhknecht L, Schönfeld C, Görsch E, Tibello A, Menck K, Bleckmann A, Lengerke C, Rosenbauer F, Grau M, Zampieri M, Schulze-Osthoff K, Klener P, Dolnikova A, Lenz G, Hailfinger S. BRD4 inhibition sensitizes diffuse large B-cell lymphoma cells to ferroptosis. Blood 2023; 142:1143-1155. [PMID: 37294920 DOI: 10.1182/blood.2022019274] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 05/16/2023] [Accepted: 05/23/2023] [Indexed: 06/11/2023] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, is characterized by an aggressive clinical course. In approximately one-third of patients with DLBCL, first-line multiagent immunochemotherapy fails to produce a durable response. Molecular heterogeneity and apoptosis resistance pose major therapeutic challenges in DLBCL treatment. To circumvent apoptosis resistance, the induction of ferroptosis might represent a promising strategy for lymphoma therapy. In this study, a compound library, targeting epigenetic modulators, was screened to identify ferroptosis-sensitizing drugs. Strikingly, bromodomain and extra-terminal domain (BET) inhibitors sensitized cells of the germinal center B-cell-like (GCB) subtype of DLBCL to ferroptosis induction and the combination of BET inhibitors with ferroptosis inducers, such as dimethyl fumarate or RSL3, synergized in the killing of DLBCL cells in vitro and in vivo. On the molecular level, the BET protein BRD4 was found to be an essential regulator of ferroptosis suppressor protein 1 expression and thus to protect GCB-DLBCL cells from ferroptosis. Collectively, we identified and characterized BRD4 as an important player in ferroptosis suppression in GCB-DLBCL and provide a rationale for the combination of BET inhibitors with ferroptosis-inducing agents as a novel therapeutic approach for DLBCL treatment.
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Affiliation(s)
- Anja Schmitt
- Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
| | - Melanie Grimm
- Department of Molecular Medicine, Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
| | - Nina Kreienkamp
- Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
| | - Hannah Junge
- Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
| | - Jan Labisch
- Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
| | | | - Caroline Schönfeld
- Department of Molecular Medicine, Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
| | - Elsa Görsch
- Department for Internal Medicine, Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
| | - Alessia Tibello
- Institute of Molecular Tumor Biology, Faculty of Medicine, University of Münster, Münster, Germany
| | - Kerstin Menck
- Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
| | - Annalen Bleckmann
- Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
| | - Claudia Lengerke
- Department for Internal Medicine, Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
| | - Frank Rosenbauer
- Institute of Molecular Tumor Biology, Faculty of Medicine, University of Münster, Münster, Germany
| | - Michael Grau
- Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
| | - Mattia Zampieri
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Klaus Schulze-Osthoff
- Department of Molecular Medicine, Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
- German Cancer Consortium (Deutsches Konsortium für Translationale Krebsforschung) and German Cancer Research Center (Deutsches Krebsforschungszentrum), Heidelberg, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany
| | - Pavel Klener
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic
- First Department of Medicine, Hematology, University General Hospital and First Faculty of Medicine, Charles University Prague, Prague, Czech Republic
| | - Alexandra Dolnikova
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic
| | - Georg Lenz
- Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
| | - Stephan Hailfinger
- Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
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23
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Wu T, Hou H, Dey A, Bachu M, Chen X, Wisniewski J, Kudoh F, Chen C, Chauhan S, Xiao H, Pan R, Ozato K. BRD4 directs mitotic cell division by inhibiting DNA damage. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.02.547436. [PMID: 37546888 PMCID: PMC10401944 DOI: 10.1101/2023.07.02.547436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/08/2023]
Abstract
BRD4 binds to acetylated histones to regulate transcription and drive cancer cell proliferation. However, the role of BRD4 in normal cell growth remains to be elucidated. Here we investigated the question by using mouse embryonic fibroblasts with conditional Brd4 knockout (KO). We found that Brd4KO cells grow more slowly than wild type cells: they do not complete replication, fail to achieve mitosis, and exhibit extensive DNA damage throughout all cell cycle stages. BRD4 was required for expression of more than 450 cell cycle genes including genes encoding core histones and centromere/kinetochore proteins that are critical for genome replication and chromosomal segregation. Moreover, we show that many genes controlling R-loop formation and DNA damage response (DDR) require BRD4 for expression. Finally, BRD4 constitutively occupied genes controlling R-loop, DDR and cell cycle progression. We suggest that BRD4 epigenetically marks those genes and serves as a master regulator of normal cell growth.
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24
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Moreno V, Vieito M, Sepulveda JM, Galvao V, Hernández-Guerrero T, Doger B, Saavedra O, Carlo-Stella C, Michot JM, Italiano A, Magagnoli M, Carpio C, Pinto A, Sarmiento R, Amoroso B, Aronchik I, Filvaroff E, Hanna B, Wei X, Nikolova Z, Braña I. BET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas. Nat Commun 2023; 14:1359. [PMID: 36914652 PMCID: PMC10011554 DOI: 10.1038/s41467-023-36976-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 02/23/2023] [Indexed: 03/16/2023] Open
Abstract
Bromodomain and extraterminal proteins (BET) play key roles in regulation of gene expression, and may play a role in cancer-cell proliferation, survival, and oncogenic progression. CC-90010-ST-001 (NCT03220347) is an open-label phase I study of trotabresib, an oral BET inhibitor, in heavily pretreated patients with advanced solid tumors and relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Primary endpoints were the safety, tolerability, maximum tolerated dose, and RP2D of trotabresib. Secondary endpoints were clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] of ≥4 months' duration), objective response rate (CR + PR), duration of response or SD, progression-free survival, overall survival, and the pharmacokinetics (PK) of trotabresib. In addition, part C assessed the effects of food on the PK of trotabresib as a secondary endpoint. The dose escalation (part A) showed that trotabresib was well tolerated, had single-agent activity, and determined the recommended phase 2 dose (RP2D) and schedule for the expansion study. Here, we report long-term follow-up results from part A (N = 69) and data from patients treated with the RP2D of 45 mg/day 4 days on/24 days off or an alternate RP2D of 30 mg/day 3 days on/11 days off in the dose-expansion cohorts (parts B [N = 25] and C [N = 41]). Treatment-related adverse events (TRAEs) are reported in almost all patients. The most common severe TRAEs are hematological. Toxicities are generally manageable, allowing some patients to remain on treatment for ≥2 years, with two patients receiving ≥3 years of treatment. Trotabresib monotherapy shows antitumor activity, with an ORR of 13.0% (95% CI, 2.8-33.6) in patients with R/R DLBCL (part B) and an ORR of 0.0% (95% CI, 0.0-8.6) and a CBR of 31.7% (95% CI, 18.1-48.1) in patients with advanced solid tumors (part C). These results support further investigation of trotabresib in combination with other anticancer agents.
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Affiliation(s)
- Victor Moreno
- START Madrid-FJD, Hospital Universitario Fundación Jimenez Diaz, Madrid, Spain.
| | - Maria Vieito
- Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | | | - Vladimir Galvao
- Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | | | - Bernard Doger
- START Madrid-FJD, Hospital Universitario Fundación Jimenez Diaz, Madrid, Spain
| | - Omar Saavedra
- Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Carmelo Carlo-Stella
- Department of Biological Sciences, Humanitas University, Rozzano, Milano, Italy
- Department of Oncology and Hematology, Humanitas Research Hospital - IRCCS, Rozzano, Milano, Italy
| | | | - Antoine Italiano
- Institut Bergonie Centre Regional de Lutte Contre Le Cancer de Bordeaux et Sud Ouest, Bordeaux, France
| | - Massimo Magagnoli
- Department of Oncology and Hematology, Humanitas Research Hospital - IRCCS, Rozzano, Milano, Italy
| | - Cecilia Carpio
- Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Antonio Pinto
- Hematology-Oncology & Stem Cell Transplantation Unit, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples, Italy
| | - Rafael Sarmiento
- Centre for Innovation and Translational Research Europe, a Bristol Myers Squibb Company, Seville, Spain
| | - Barbara Amoroso
- Centre for Innovation and Translational Research Europe, a Bristol Myers Squibb Company, Seville, Spain
| | | | | | | | - Xin Wei
- Bristol Myers Squibb, Princeton, NJ, USA
| | - Zariana Nikolova
- Centre for Innovation and Translational Research Europe, a Bristol Myers Squibb Company, Seville, Spain
| | - Irene Braña
- Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
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25
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Zhang M, Li Y, Zhang Z, Zhang X, Wang W, Song X, Zhang D. BRD4 Protein as a Target for Lung Cancer and Hematological Cancer Therapy: A Review. Curr Drug Targets 2023; 24:1079-1092. [PMID: 37846578 DOI: 10.2174/0113894501269090231012090351] [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: 06/28/2023] [Revised: 08/30/2023] [Accepted: 09/15/2023] [Indexed: 10/18/2023]
Abstract
The BET protein family plays a crucial role in regulating the epigenetic landscape of the genome. Their role in regulating tumor-related gene expression and its impact on the survival of tumor cells is widely acknowledged. Among the BET family constituents, BRD4 is a significant protein. It is a bromodomain-containing protein located at the outer terminal that recognizes histones that have undergone acetylation. It is present in the promoter or enhancer region of the target gene and is responsible for initiating and sustaining the expression of genes associated with tumorigenesis. BRD4 expression is significantly elevated in various tumor types. Research has indicated that BRD4 plays a significant role in regulating various transcription factors and chromatin modification, as well as in repairing DNA damage and preserving telomere function, ultimately contributing to the survival of cancerous cells. The protein BRD4 has a significant impact on antitumor therapy, particularly in the management of lung cancer and hematological malignancies, and the promising potential of BRD4 inhibitors in the realm of cancer prevention and treatment is a topic of great interest. Therefore, BRD4 is considered a promising candidate for prophylaxis and therapy of neoplastic diseases. However, further research is required to fully comprehend the significance and indispensability of BRD4 in cancer and its potential as a therapeutic target.
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Affiliation(s)
- Mengmeng Zhang
- College of Humanities and Management, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712046, P.R. China
| | - Yingbo Li
- College of Humanities and Management, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712046, P.R. China
| | - Zilong Zhang
- School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712046, P.R. China
| | - Xin Zhang
- School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712046, P.R. China
| | - Wei Wang
- School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712046, P.R. China
| | - Xiaomei Song
- School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712046, P.R. China
| | - Dongdong Zhang
- School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712046, P.R. China
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26
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Ali HA, Li Y, Bilal AHM, Qin T, Yuan Z, Zhao W. A Comprehensive Review of BET Protein Biochemistry, Physiology, and Pathological Roles. Front Pharmacol 2022; 13:818891. [PMID: 35401196 PMCID: PMC8990909 DOI: 10.3389/fphar.2022.818891] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 01/26/2022] [Indexed: 11/13/2022] Open
Abstract
Epigenetic modifications, specifically acetylation of histone plays a decisive role in gene regulation and transcription of normal cellular mechanisms and pathological conditions. The bromodomain and extraterminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT), being epigenetic readers, ligate to acetylated regions of histone and synchronize gene transcription. BET proteins are crucial for normal cellular processing as they control cell cycle progression, neurogenesis, differentiation, and maturation of erythroids and spermatogenesis, etc. Research-based evidence indicated that BET proteins (mainly BRD4) are associated with numeral pathological ailments, including cancer, inflammation, infections, renal diseases, and cardiac diseases. To counter the BET protein-related pathological conditions, there are some BET inhibitors developed and also under development. BET proteins are a topic of most research nowadays. This review, provides an ephemeral but comprehensive knowledge about BET proteins’ basic structure, biochemistry, physiological roles, and pathological conditions in which the role of BETs have been proven. This review also highlights the current and future approaches to pledge BET protein-related pathologies.
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Affiliation(s)
- Hafiz Akbar Ali
- Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.,Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yalan Li
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Akram Hafiz Muhammad Bilal
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Tingting Qin
- Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Ziqiao Yuan
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Wen Zhao
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China
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27
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Lemelle L, Moya-Plana A, Dumont B, Fresneau B, Laprie A, Claude L, Deneuve S, Cordero C, Pierron G, Couloigner V, Bernard S, Cardoen L, Brisse HJ, Jehanno N, Metayer L, Fréneaux P, Helfre S, Kolb F, Thariat J, Réguerre Y, Orbach D. NUT carcinoma in children, adolescents and young adults. Bull Cancer 2022; 109:491-504. [DOI: 10.1016/j.bulcan.2022.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 01/22/2022] [Accepted: 01/31/2022] [Indexed: 10/18/2022]
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28
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Albarnaz JD, Ren H, Torres AA, Shmeleva EV, Melo CA, Bannister AJ, Brember MP, Chung BYW, Smith GL. Molecular mimicry of NF-κB by vaccinia virus protein enables selective inhibition of antiviral responses. Nat Microbiol 2022; 7:154-168. [PMID: 34949827 PMCID: PMC7614822 DOI: 10.1038/s41564-021-01004-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 10/21/2021] [Indexed: 12/16/2022]
Abstract
Infection of mammalian cells with viruses activates NF-κB to induce the expression of cytokines and chemokines and initiate an antiviral response. Here, we show that a vaccinia virus protein mimics the transactivation domain of the p65 subunit of NF-κB to inhibit selectively the expression of NF-κB-regulated genes. Using co-immunoprecipitation assays, we found that the vaccinia virus protein F14 associates with NF-κB co-activator CREB-binding protein (CBP) and disrupts the interaction between p65 and CBP. This abrogates CBP-mediated acetylation of p65, after which it reduces promoter recruitment of the transcriptional regulator BRD4 and diminishes stimulation of NF-κB-regulated genes CXCL10 and CCL2. Recruitment of BRD4 to the promoters of NFKBIA and CXCL8 remains unaffected by either F14 or JQ1 (a competitive inhibitor of BRD4 bromodomains), indicating that BRD4 recruitment is acetylation-independent. Unlike other viral proteins that are general antagonists of NF-κB, F14 is a selective inhibitor of NF-κB-dependent gene expression. An in vivo model of infection demonstrated that F14 promotes virulence. Molecular mimicry of NF-κB may be conserved because other orthopoxviruses, including variola, monkeypox and cowpox viruses, encode orthologues of F14.
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Affiliation(s)
- Jonas D Albarnaz
- Department of Pathology, University of Cambridge, Cambridge, UK.
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
| | - Hongwei Ren
- Department of Pathology, University of Cambridge, Cambridge, UK
- Department of Immunology and Inflammation, Imperial College London, Hammersmith Campus, London, UK
| | - Alice A Torres
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Evgeniya V Shmeleva
- Department of Pathology, University of Cambridge, Cambridge, UK
- Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, UK
| | - Carlos A Melo
- The Gurdon Institute, University of Cambridge, Cambridge, UK
| | | | | | - Betty Y-W Chung
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Geoffrey L Smith
- Department of Pathology, University of Cambridge, Cambridge, UK.
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29
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Zhou K, Zhuang S, Liu F, Chen Y, Li Y, Wang S, Li Y, Wen H, Lin X, Wang J, Huang Y, He C, Xu N, Li Z, Xu L, Zhang Z, Chen LF, Chen R, Liu M. Disrupting the Cdk9/Cyclin T1 heterodimer of 7SK snRNP for the Brd4 and AFF1/4 guided reconstitution of active P-TEFb. Nucleic Acids Res 2021; 50:750-762. [PMID: 34935961 PMCID: PMC8789079 DOI: 10.1093/nar/gkab1228] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 11/23/2021] [Accepted: 12/10/2021] [Indexed: 01/16/2023] Open
Abstract
P-TEFb modulates RNA polymerase II elongation through alternative interaction with negative and positive regulation factors. While inactive P-TEFbs are mainly sequestered in the 7SK snRNP complex in a chromatin-free state, most of its active forms are in complex with its recruitment factors, Brd4 and SEC, in a chromatin-associated state. Thus, switching from inactive 7SK snRNP to active P-TEFb (Brd4/P-TEFb or SEC/P-TEFb) is essential for global gene expression. Although it has been shown that cellular signaling stimulates the disruption of 7SK snRNP, releasing dephosphorylated and catalytically inactive P-TEFb, little is known about how the inactive released P-TEFb is reactivated. Here, we show that the Cdk9/CycT1 heterodimer released from 7SK snRNP is completely dissociated into monomers in response to stress. Brd4 or SEC then recruits monomerized Cdk9 and CycT1 to reassemble the core P-TEFb. Meanwhile, the binding of monomeric dephosphorylated Cdk9 to either Brd4 or SEC induces the autophosphorylation of T186 of Cdk9. Finally, the same mechanism is employed during nocodazole released entry into early G1 phase of cell cycle. Therefore, our studies demonstrate a novel mechanism by which Cdk9 and CycT1 monomers are reassembled on chromatin to form active P-TEFb by its interaction with Brd4 or SEC to regulate transcription.
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Affiliation(s)
- Kai Zhou
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China
| | - Songkuan Zhuang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China
| | - Fulong Liu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China
| | - Yanheng Chen
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - You Li
- Biomolecular Interaction Centre, University of Canterbury, Christchurch 8140, New Zealand
| | - Shihui Wang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China
| | - Yuxuan Li
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China
| | - Huixin Wen
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China
| | - Xiaohua Lin
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China
| | - Jie Wang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China
| | - Yue Huang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China
| | - Cailing He
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China
| | - Nan Xu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China
| | - Zongshu Li
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China
| | - Lang Xu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China
| | - Zixuan Zhang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China
| | - Lin-Feng Chen
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Ruichuan Chen
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China
| | - Min Liu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China
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30
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Oncogenic Truncations of ASXL1 Enhance a Motif for BRD4 ET-Domain Binding. J Mol Biol 2021; 433:167242. [PMID: 34536441 DOI: 10.1016/j.jmb.2021.167242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 09/04/2021] [Accepted: 09/07/2021] [Indexed: 11/23/2022]
Abstract
Proper regulation of gene-expression relies on specific protein-protein interactions between a myriad of epigenetic regulators. As such, mutation of genes encoding epigenetic regulators often drive cancer and developmental disorders. Additional sex combs-like protein 1 (ASXL1) is a key example, where mutations frequently drive haematological cancers and can cause developmental disorders. It has been reported that nonsense mutations in ASXL1 promote an interaction with BRD4, another central epigenetic regulator. Here we provide a molecular mechanism for the BRD4-ASXL1 interaction, demonstrating that a motif near to common truncation breakpoints of ASXL1 contains an epitope that binds the ET domain within BRD4. Binding-studies show that this interaction is analogous to common ET-binding modes of BRD4-interactors, and that all three ASX-like protein orthologs (ASXL1-3) contain a functional ET domain-binding epitope. Crucially, we observe that BRD4-ASXL1 binding is markedly increased in the prevalent ASXL1Y591X truncation that maintains the BRD4-binding epitope, relative to full-length ASXL1 or truncated proteins that delete the epitope. Together, these results show that ASXL1 truncation enhances BRD4 recruitment to transcriptional complexes via its ET domain, which could misdirect regulatory activity of either BRD4 or ASXL1 and may inform potential therapeutic interventions.
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31
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Niu H, Song F, Wei H, Li Y, Huang H, Wu C. Inhibition of BRD4 Suppresses the Growth of Esophageal Squamous Cell Carcinoma. Cancer Invest 2021; 39:826-841. [PMID: 34519605 DOI: 10.1080/07357907.2021.1975736] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Bromodomain-containing protein 4 (BRD4) binds acetylated lysine residues on histones to facilitate the epigenetic regulation of many genes, and it plays a key role in many cancer types. Despite many prior reports that have explored the importance of BRD4 in oncogenesis and the regulation of epigenetic memory, its role in esophageal squamous cell carcinoma (ESCC) progression is poorly understood. Here, we investigated BRD4 expression in human ESCC tissues to understand how it regulates the biology of these tumor cells. METHODS BRD4 expression in ESCC tissues was measured via immunohistochemical staining. BRD4 inhibition in the Eca-109 and KYSE-150 ESCC cell lines was conducted to explore its functional role in these tumor cells. RESULTS BRD4 overexpression was observed in ESCC tissues and cells, and inhibiting the function of the gene impaired the proliferative, invasive, and migratory activity of these cells while promoting their apoptosis. Cyclin D1 and c-Myc expression were also suppressed by BRD4 inhibition, and the expression of key epithelial-mesenchymal transition markers including E-cadherin and Vimentin was markedly altered by such inhibition. CONCLUSIONS BRD4 plays key functional roles in the biology of ESCC, proposing that it could be a viable therapeutic target for treating this cancer type.
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Affiliation(s)
- Haiyu Niu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Oncology, Lanzhou University Second Hospital, Lanzhou, China.,Institute of Cell Therapy, Soochow University, Changzhou, China
| | - Feixue Song
- Department of Oncology, Lanzhou University Second Hospital, Lanzhou, China
| | - Hanwen Wei
- Department of Cardiology, The First People's Hospital of Lanzhou, Lanzhou, China
| | - Yuan Li
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Institute of Cell Therapy, Soochow University, Changzhou, China
| | - Hao Huang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Institute of Cell Therapy, Soochow University, Changzhou, China
| | - Changping Wu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Institute of Cell Therapy, Soochow University, Changzhou, China.,Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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32
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Lara-Ureña N, García-Domínguez M. Relevance of BET Family Proteins in SARS-CoV-2 Infection. Biomolecules 2021; 11:1126. [PMID: 34439792 PMCID: PMC8391731 DOI: 10.3390/biom11081126] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/22/2021] [Accepted: 07/27/2021] [Indexed: 12/14/2022] Open
Abstract
The recent pandemic we are experiencing caused by the coronavirus disease 2019 (COVID-19) has put the world's population on the rack, with more than 191 million cases and more than 4.1 million deaths confirmed to date. This disease is caused by a new type of coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A massive proteomic analysis has revealed that one of the structural proteins of the virus, the E protein, interacts with BRD2 and BRD4 proteins of the Bromodomain and Extra Terminal domain (BET) family of proteins. BETs are essential to cell cycle progression, inflammation and immune response and have also been strongly associated with infection by different types of viruses. The fundamental role BET proteins play in transcription makes them appropriate targets for the propagation strategies of some viruses. Recognition of histone acetylation by BET bromodomains is essential for transcription control. The development of drugs mimicking acetyl groups, and thereby able to displace BET proteins from chromatin, has boosted interest on BETs as attractive targets for therapeutic intervention. The success of these drugs against a variety of diseases in cellular and animal models has been recently enlarged with promising results from SARS-CoV-2 infection studies.
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Affiliation(s)
| | - Mario García-Domínguez
- Andalusian Centre for Molecular Biology and Regenerative Medicine (CABIMER), CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Av. Américo Vespucio 24, 41092 Seville, Spain;
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33
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García-Gutiérrez P, García-Domínguez M. BETting on a Transcriptional Deficit as the Main Cause for Cornelia de Lange Syndrome. Front Mol Biosci 2021; 8:709232. [PMID: 34386522 PMCID: PMC8353280 DOI: 10.3389/fmolb.2021.709232] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 07/16/2021] [Indexed: 12/12/2022] Open
Abstract
Cornelia de Lange Syndrome (CdLS) is a human developmental syndrome with complex multisystem phenotypic features. It has been traditionally considered a cohesinopathy together with other phenotypically related diseases because of their association with mutations in subunits of the cohesin complex. Despite some overlap, the clinical manifestations of cohesinopathies vary considerably and, although their precise molecular mechanisms are not well defined yet, the potential pathomechanisms underlying these diverse developmental defects have been theoretically linked to alterations of the cohesin complex function. The cohesin complex plays a critical role in sister chromatid cohesion, but this function is not affected in CdLS. In the last decades, a non-cohesion-related function of this complex on transcriptional regulation has been well established and CdLS pathoetiology has been recently associated to gene expression deregulation. Up to 70% of CdLS cases are linked to mutations in the cohesin-loading factor NIPBL, which has been shown to play a prominent function on chromatin architecture and transcriptional regulation. Therefore, it has been suggested that CdLS can be considered a transcriptomopathy. Actually, CdLS-like phenotypes have been associated to mutations in chromatin-associated proteins, as KMT2A, AFF4, EP300, TAF6, SETD5, SMARCB1, MAU2, ZMYND11, MED13L, PHIP, ARID1B, NAA10, BRD4 or ANKRD11, most of which have no known direct association with cohesin. In the case of BRD4, a critical highly investigated transcriptional coregulator, an interaction with NIPBL has been recently revealed, providing evidence on their cooperation in transcriptional regulation of developmentally important genes. This new finding reinforces the notion of an altered gene expression program during development as the major etiological basis for CdLS. In this review, we intend to integrate the recent available evidence on the molecular mechanisms underlying the clinical manifestations of CdLS, highlighting data that favors a transcription-centered framework, which support the idea that CdLS could be conceptualized as a transcriptomopathy.
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Affiliation(s)
- Pablo García-Gutiérrez
- Andalusian Centre for Molecular Biology and Regenerative Medicine-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Seville, Spain
| | - Mario García-Domínguez
- Andalusian Centre for Molecular Biology and Regenerative Medicine-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Seville, Spain
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34
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Shiota H, Alekseyenko AA, Wang ZA, Filic I, Knox TM, Luong NM, Huang Y, Scott DA, Jones KL, Gokhale PC, Lemieux ME, Cole PA, Kuroda MI, French CA. Chemical Screen Identifies Diverse and Novel Histone Deacetylase Inhibitors as Repressors of NUT Function: Implications for NUT Carcinoma Pathogenesis and Treatment. Mol Cancer Res 2021; 19:1818-1830. [PMID: 34285087 DOI: 10.1158/1541-7786.mcr-21-0259] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/23/2021] [Accepted: 07/16/2021] [Indexed: 11/16/2022]
Abstract
NUT carcinoma (NC), characterized most commonly by the BRD4-NUTM1 fusion, is a rare, aggressive variant of squamous carcinoma with no effective treatment. BRD4-NUT drives growth and maintains the poorly differentiated state of NC by activating pro-growth genes such as MYC, through the formation of massive, hyperacetylated, superenhancer-like domains termed megadomains. BRD4-NUT-mediated hyperacetylation of chromatin is facilitated by the chromatin-targeting tandem bromodomains of BRD4, combined with NUT, which recruits the histone acetyltransferase, p300. Here, we developed a high-throughput small-molecule screen to identify inhibitors of transcriptional activation by NUT. In this dCAS9-based GFP-reporter assay, the strongest hits were diverse histone deacetylase (HDAC) inhibitors. Two structurally unrelated HDAC inhibitors, panobinostat and the novel compound, IRBM6, both repressed growth and induced differentiation of NC cells in proportion to their inhibition of NUT transcriptional activity. These two compounds repressed transcription of megadomain-associated oncogenic genes, such as MYC and SOX2, while upregulating pro-differentiation, non-megadomain-associated genes, including JUN, FOS, and key cell-cycle regulators, such as CDKN1A. The transcriptional changes correlate with depletion of BRD4-NUT from megadomains, and redistribution of the p300/CBP-associated chromatin acetylation mark, H3K27ac, away from megadomains toward regular enhancer regions previously populated by H3K27ac. In NC xenograft models, we demonstrated that suppression of tumor growth by panobinostat was comparable with that of bromodomain inhibition, and when combined they improved both survival and growth suppression. IMPLICATIONS: The findings provide mechanistic and preclinical rationale for the use of HDAC inhibitors, alone or combined with other agents, in the treatment of NUT carcinoma.
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Affiliation(s)
- Hitoshi Shiota
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Artyom A Alekseyenko
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.,Department of Genetics, Harvard Medical School, Boston, Massachusetts
| | - Zhipeng A Wang
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts
| | - Ivona Filic
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Tatiana M Knox
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Nhi M Luong
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Yeying Huang
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - David A Scott
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts
| | - Kristen L Jones
- Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Prafulla C Gokhale
- Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | | | - Philip A Cole
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts
| | - Mitzi I Kuroda
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.,Department of Genetics, Harvard Medical School, Boston, Massachusetts
| | - Christopher A French
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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35
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Mochizuki K, Ishiyama S, Hariya N, Goda T. Regulation of Carbohydrate-Responsive Metabolic Genes by Histone Acetylation and the Acetylated Histone Reader BRD4 in the Gene Body Region. Front Mol Biosci 2021; 8:682696. [PMID: 34336926 PMCID: PMC8321877 DOI: 10.3389/fmolb.2021.682696] [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: 03/19/2021] [Accepted: 06/30/2021] [Indexed: 11/17/2022] Open
Abstract
Studies indicate that induction of metabolic gene expression by nutrient intake, and in response to subsequently secreted hormones, is regulated by transcription factors binding to cis-elements and associated changes of epigenetic memories (histone modifications and DNA methylation) located in promoter and enhancer regions. Carbohydrate intake-mediated induction of metabolic gene expression is regulated by histone acetylation and the histone acetylation reader bromodomain-containing protein 4 (BRD4) on the gene body region, which corresponds to the transcribed region of the gene. In this review, we introduce carbohydrate-responsive metabolic gene regulation by (i) transcription factors and epigenetic memory in promoter/enhancer regions (promoter/enhancer-based epigenetics), and (ii) histone acetylation and BRD4 in the gene body region (gene body-based epigenetics). Expression of carbohydrate-responsive metabolic genes related to nutrient digestion and absorption, fat synthesis, inflammation in the small intestine, liver and white adipose tissue, and in monocytic/macrophage-like cells are regulated by various transcription factors. The expression of these metabolic genes are also regulated by transcription elongation via histone acetylation and BRD4 in the gene body region. Additionally, the expression of genes related to fat synthesis, and the levels of acetylated histones and BRD4 in fat synthesis-related genes, are downregulated in white adipocytes under insulin resistant and/or diabetic conditions. In contrast, expression of carbohydrate-responsive metabolic genes and/or histone acetylation and BRD4 binding in the gene body region of these genes, are upregulated in the small intestine, liver, and peripheral leukocytes (innate leukocytes) under insulin resistant and/or diabetic conditions. In conclusion, histone acetylation and BRD4 binding in the gene body region as well as transcription factor binding in promoter/enhancer regions regulate the expression of carbohydrate-responsive metabolic genes in many metabolic organs. Insulin resistant and diabetic conditions induce the development of metabolic diseases, including type 2 diabetes, by reducing the expression of BRD4-targeted carbohydrate-responsive metabolic genes in white adipose tissue and by inducing the expression of BRD4-targeted carbohydrate-responsive metabolic genes in the liver, small intestine, and innate leukocytes including monocytes/macrophages and neutrophils.
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Affiliation(s)
- Kazuki Mochizuki
- Department of Local Produce and Food Sciences, Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi, Japan
- Department of Integrated Applied Life Science, Integrated Graduate School of Medicine, Engineering, and Agricultural Sciences, University of Yamanashi, Yamanashi, Japan
| | - Shiori Ishiyama
- Department of Integrated Applied Life Science, Integrated Graduate School of Medicine, Engineering, and Agricultural Sciences, University of Yamanashi, Yamanashi, Japan
| | - Natsuyo Hariya
- Department of Nutrition, Faculty of Health and Nutrition, Yamanashi Gakuin University, Yamanashi, Japan
| | - Toshinao Goda
- Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, Shizuoka, Japan
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The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells. Hemasphere 2021; 5:e610. [PMID: 34258514 PMCID: PMC8265862 DOI: 10.1097/hs9.0000000000000610] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 06/02/2021] [Indexed: 11/25/2022] Open
Abstract
Acute myeloid leukemia (AML) is a disease characterized by transcriptional dysregulation that results in a block in differentiation and aberrant self-renewal. Inhibitors directed to epigenetic modifiers, aiming at transcriptional reprogramming of AML cells, are currently in clinical trials for AML patients. Several of these inhibitors target bromodomain and extraterminal domain (BET) proteins, cyclic AMP response binding protein-binding protein (CBP), and the E1A-interacting protein of 300 kDa (p300), affecting histone acetylation. Unfortunately, single epigenetic inhibitors showed limited efficacy due to appearance of resistance and lack of effective eradication of leukemic stem cells. Here, we describe the efficacy of 2 novel, orally available inhibitors targeting both the BET and CBP/p300 proteins, NEO1132 and NEO2734, in primary AML. NEO2734 and NEO1132 efficiently reduced the viability of AML cell lines and primary AML cells by inducing apoptosis. Importantly, both NEO drugs eliminated leukemic stem/progenitor cells from AML patient samples, and NEO2734 increased the effectiveness of combination chemotherapy treatment in an in vivo AML patient-derived mouse model. Thus, dual inhibition of BET and CBP/p300 using NEO2734 is a promising therapeutic strategy for AML patients, making it a focus for clinical translation.
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37
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Mandhair HK, Novak U, Radpour R. Epigenetic regulation of autophagy: A key modification in cancer cells and cancer stem cells. World J Stem Cells 2021; 13:542-567. [PMID: 34249227 PMCID: PMC8246247 DOI: 10.4252/wjsc.v13.i6.542] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/02/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Aberrant epigenetic alterations play a decisive role in cancer initiation and propagation via the regulation of key tumor suppressor genes and oncogenes or by modulation of essential signaling pathways. Autophagy is a highly regulated mechanism required for the recycling and degradation of surplus and damaged cytoplasmic constituents in a lysosome dependent manner. In cancer, autophagy has a divergent role. For instance, autophagy elicits tumor promoting functions by facilitating metabolic adaption and plasticity in cancer stem cells (CSCs) and cancer cells. Moreover, autophagy exerts pro-survival mechanisms to these cancerous cells by influencing survival, dormancy, immunosurveillance, invasion, metastasis, and resistance to anti-cancer therapies. In addition, recent studies have demonstrated that various tumor suppressor genes and oncogenes involved in autophagy, are tightly regulated via different epigenetic modifications, such as DNA methylation, histone modifications and non-coding RNAs. The impact of epigenetic regulation of autophagy in cancer cells and CSCs is not well-understood. Therefore, uncovering the complex mechanism of epigenetic regulation of autophagy provides an opportunity to improve and discover novel cancer therapeutics. Subsequently, this would aid in improving clinical outcome for cancer patients. In this review, we provide a comprehensive overview of the existing knowledge available on epigenetic regulation of autophagy and its importance in the maintenance and homeostasis of CSCs and cancer cells.
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Affiliation(s)
- Harpreet K Mandhair
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Urban Novak
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Ramin Radpour
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
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38
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Shrestha S, Morcavallo A, Gorrini C, Chesler L. Biological Role of MYCN in Medulloblastoma: Novel Therapeutic Opportunities and Challenges Ahead. Front Oncol 2021; 11:694320. [PMID: 34195095 PMCID: PMC8236857 DOI: 10.3389/fonc.2021.694320] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 05/19/2021] [Indexed: 12/13/2022] Open
Abstract
The constitutive and dysregulated expression of the transcription factor MYCN has a central role in the pathogenesis of the paediatric brain tumour medulloblastoma, with an increased expression of this oncogene correlating with a worse prognosis. Consequently, the genomic and functional alterations of MYCN represent a major therapeutic target to attenuate tumour growth in medulloblastoma. This review will provide a comprehensive synopsis of the biological role of MYCN and its family components, their interaction with distinct signalling pathways, and the implications of this network in medulloblastoma development. We will then summarise the current toolbox for targeting MYCN and highlight novel therapeutic avenues that have the potential to results in better-tailored clinical treatments.
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Affiliation(s)
- Sumana Shrestha
- Division of Clinical Studies, Institute of Cancer Research (ICR), London and Royal Marsden NHS Trust, Sutton, United Kingdom
| | - Alaide Morcavallo
- Division of Clinical Studies, Institute of Cancer Research (ICR), London and Royal Marsden NHS Trust, Sutton, United Kingdom
| | - Chiara Gorrini
- Division of Clinical Studies, Institute of Cancer Research (ICR), London and Royal Marsden NHS Trust, Sutton, United Kingdom
| | - Louis Chesler
- Division of Clinical Studies, Institute of Cancer Research (ICR), London and Royal Marsden NHS Trust, Sutton, United Kingdom.,Division of Cancer Therapeutics, The Institute of Cancer Research (ICR), and The Royal Marsden NHS Trust, Sutton, United Kingdom
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39
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Zhang S, Chen Y, Tian C, He Y, Tian Z, Wan Y, Liu T. Dual-target Inhibitors Based on BRD4: Novel Therapeutic Approaches for Cancer. Curr Med Chem 2021; 28:1775-1795. [PMID: 32520674 DOI: 10.2174/0929867327666200610174453] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 03/30/2020] [Accepted: 04/06/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Currently, cancer continues being a dramatically increasing and serious threat to public health. Although many anti-tumor agents have been developed in recent years, the survival rate of patients is not satisfactory. The poor prognosis of cancer patients is closely related to the occurrence of drug resistance. Therefore, it is urgent to develop new strategies for cancer treatment. Multi-target therapies aim to have additive or synergistic effects and reduce the potential for the development of resistance by integrating different pharmacophores into a single drug molecule. Given the fact that majority of diseases are multifactorial in nature, multi-target therapies are being exploited with increasing intensity, which has brought improved outcomes in disease models and obtained several compounds that have entered clinical trials. Thus, it is potential to utilize this strategy for the treatment of BRD4 related cancers. This review focuses on the recent research advances of dual-target inhibitors based on BRD4 in the aspect of anti-tumor. METHODS We have searched the recent literatures about BRD4 inhibitors from the online resources and databases, such as pubmed, elsevier and google scholar. RESULTS In the recent years, many efforts have been taken to develop dual-target inhibitors based on BRD4 as anti-cancer agents, such as HDAC/BRD4 dual inhibitors, PLK1/BRD4 dual inhibitors and PI3K/BRD4 dual inhibitors and so on. Most compounds display good anti-tumor activities. CONCLUSION Developing new anti-cancer agents with new scaffolds and high efficiency is a big challenge for researchers. Dual-target inhibitors based on BRD4 are a class of important bioactive compounds. Making structural modifications on the active dual-target inhibitors according to the corresponding structure-activity relationships is of benefit to obtain more potent anti-cancer leads or clinical drugs. This review will be useful for further development of new dual-target inhibitors based on BRD4 as anti-cancer agents.
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Affiliation(s)
- Sitao Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271000, Shandong, China
| | - Yanzhao Chen
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271000, Shandong, China
| | - Chengsen Tian
- School of Chemistry and Chemical Engineering, Qilu Normal University, Jinan, Shandong 250200, China
| | - Yujing He
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271000, Shandong, China
| | - Zeru Tian
- Department of Chemistry, Rice University, 6100 Main Street, Houston, Texas 77005, United States
| | - Yichao Wan
- Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, Ministry of Education, Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, China
| | - Tingting Liu
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271000, Shandong, China
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40
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Anshabo AT, Milne R, Wang S, Albrecht H. CDK9: A Comprehensive Review of Its Biology, and Its Role as a Potential Target for Anti-Cancer Agents. Front Oncol 2021; 11:678559. [PMID: 34041038 PMCID: PMC8143439 DOI: 10.3389/fonc.2021.678559] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 04/16/2021] [Indexed: 12/25/2022] Open
Abstract
Cyclin-dependent kinases (CDKs) are proteins pivotal to a wide range of cellular functions, most importantly cell division and transcription, and their dysregulations have been implicated as prominent drivers of tumorigenesis. Besides the well-established role of cell cycle CDKs in cancer, the involvement of transcriptional CDKs has been confirmed more recently. Most cancers overtly employ CDKs that serve as key regulators of transcription (e.g., CDK9) for a continuous production of short-lived gene products that maintain their survival. As such, dysregulation of the CDK9 pathway has been observed in various hematological and solid malignancies, making it a valuable anticancer target. This therapeutic potential has been utilized for the discovery of CDK9 inhibitors, some of which have entered human clinical trials. This review provides a comprehensive discussion on the structure and biology of CDK9, its role in solid and hematological cancers, and an updated review of the available inhibitors currently being investigated in preclinical and clinical settings.
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Affiliation(s)
- Abel Tesfaye Anshabo
- Drug Discovery and Development, Centre for Cancer Diagnostics and Therapeutics, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
| | - Robert Milne
- Drug Discovery and Development, Centre for Cancer Diagnostics and Therapeutics, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
| | - Shudong Wang
- Drug Discovery and Development, Centre for Cancer Diagnostics and Therapeutics, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
| | - Hugo Albrecht
- Drug Discovery and Development, Centre for Cancer Diagnostics and Therapeutics, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
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41
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Shorstova T, Foulkes WD, Witcher M. Achieving clinical success with BET inhibitors as anti-cancer agents. Br J Cancer 2021; 124:1478-1490. [PMID: 33723398 PMCID: PMC8076232 DOI: 10.1038/s41416-021-01321-0] [Citation(s) in RCA: 224] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 01/12/2021] [Accepted: 02/11/2021] [Indexed: 12/16/2022] Open
Abstract
The transcriptional upregulation of oncogenes is a driving force behind the progression of many tumours. However, until a decade ago, the concept of 'switching off' these oncogenic pathways represented a formidable challenge. Research has revealed that members of the bromo- and extra-terminal domain (BET) motif family are key activators of oncogenic networks in a spectrum of cancers; their function depends on their recruitment to chromatin through two bromodomains (BD1 and BD2). The advent of potent inhibitors of BET proteins (BETi), which target either one or both bromodomains, represents an important step towards the goal of suppressing oncogenic networks within tumours. Here, we discuss the biology of BET proteins, advances in BETi design and highlight potential biomarkers predicting their activity. We also outline the logic of incorporating BETi into combination therapies to enhance its efficacy. We suggest that understanding mechanisms of activity, defining predictive biomarkers and identifying potent synergies represents a roadmap for clinical success using BETi.
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Affiliation(s)
- Tatiana Shorstova
- grid.414980.00000 0000 9401 2774Departments of Oncology and Experimental Medicine, McGill University, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montreal, QC Canada
| | - William D. Foulkes
- grid.414980.00000 0000 9401 2774Departments of Oncology and Human Genetics, McGill University, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montreal, QC Canada
| | - Michael Witcher
- grid.414980.00000 0000 9401 2774Departments of Oncology and Experimental Medicine, McGill University, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montreal, QC Canada
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42
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Łukasik P, Załuski M, Gutowska I. Cyclin-Dependent Kinases (CDK) and Their Role in Diseases Development-Review. Int J Mol Sci 2021; 22:ijms22062935. [PMID: 33805800 PMCID: PMC7998717 DOI: 10.3390/ijms22062935] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/07/2021] [Accepted: 03/09/2021] [Indexed: 12/13/2022] Open
Abstract
Cyclin-dependent kinases (CDKs) are involved in many crucial processes, such as cell cycle and transcription, as well as communication, metabolism, and apoptosis. The kinases are organized in a pathway to ensure that, during cell division, each cell accurately replicates its DNA, and ensure its segregation equally between the two daughter cells. Deregulation of any of the stages of the cell cycle or transcription leads to apoptosis but, if uncorrected, can result in a series of diseases, such as cancer, neurodegenerative diseases (Alzheimer’s or Parkinson’s disease), and stroke. This review presents the current state of knowledge about the characteristics of cyclin-dependent kinases as potential pharmacological targets.
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Affiliation(s)
- Paweł Łukasik
- Department of Medical Chemistry, Pomeranian Medical University in Szczecin, Powstancow Wlkp. 72 Av., 70-111 Szczecin, Poland;
| | - Michał Załuski
- Department of Pharmaceutical Chemistry, Pomeranian Medical University in Szczecin, Powstancow Wlkp. 72 Av., 70-111 Szczecin, Poland;
| | - Izabela Gutowska
- Department of Medical Chemistry, Pomeranian Medical University in Szczecin, Powstancow Wlkp. 72 Av., 70-111 Szczecin, Poland;
- Correspondence:
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43
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Li L, Xie W, Gui Y, Zheng XL. Bromodomain-containing protein 4 and its role in cardiovascular diseases. J Cell Physiol 2020; 236:4829-4840. [PMID: 33345363 DOI: 10.1002/jcp.30225] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 12/03/2020] [Accepted: 12/07/2020] [Indexed: 12/22/2022]
Abstract
Bromodomain-containing protein 4 (BRD4), a chromatin-binding protein, is involved in the development of various tumors. Recent evidence suggests that BRD4 also plays a significant role in cardiovascular diseases, such as ischemic heart disease, hypertension, and cardiac hypertrophy. This review summarizes the roles of BRD4 as a potential regulator of various pathophysiological processes in cardiovascular diseases, implicating that BRD4 may be a new therapeutic target for cardiovascular diseases in the future.
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Affiliation(s)
- Liang Li
- Department of Pathophysiology, Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, China.,Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute, Cumming School of Medicine, The University of Calgary, Calgary, Alberta, Canada
| | - Wei Xie
- Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute, Cumming School of Medicine, The University of Calgary, Calgary, Alberta, Canada.,Department of Anatomy, Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang, Hunan, China
| | - Yu Gui
- Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute, Cumming School of Medicine, The University of Calgary, Calgary, Alberta, Canada
| | - Xi-Long Zheng
- Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute, Cumming School of Medicine, The University of Calgary, Calgary, Alberta, Canada
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Pelham-Webb B, Murphy D, Apostolou E. Dynamic 3D Chromatin Reorganization during Establishment and Maintenance of Pluripotency. Stem Cell Reports 2020; 15:1176-1195. [PMID: 33242398 PMCID: PMC7724465 DOI: 10.1016/j.stemcr.2020.10.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 10/25/2020] [Accepted: 10/27/2020] [Indexed: 12/12/2022] Open
Abstract
Higher-order chromatin structure is tightly linked to gene expression and therefore cell identity. In recent years, the chromatin landscape of pluripotent stem cells has become better characterized, and unique features at various architectural levels have been revealed. However, the mechanisms that govern establishment and maintenance of these topological characteristics and the temporal and functional relationships with transcriptional or epigenetic features are still areas of intense study. Here, we will discuss progress and limitations of our current understanding regarding how the 3D chromatin topology of pluripotent stem cells is established during somatic cell reprogramming and maintained during cell division. We will also discuss evidence and theories about the driving forces of topological reorganization and the functional links with key features and properties of pluripotent stem cell identity.
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Affiliation(s)
- Bobbie Pelham-Webb
- Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY 10021, USA
| | - Dylan Murphy
- Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
| | - Effie Apostolou
- Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA.
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45
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Song Y, Hu G, Jia J, Yao M, Wang X, Lu W, Hutchins AP, Chen J, Ozato K, Yao H. DNA Damage Induces Dynamic Associations of BRD4/P-TEFb With Chromatin and Modulates Gene Transcription in a BRD4-Dependent and -Independent Manner. Front Mol Biosci 2020; 7:618088. [PMID: 33344510 PMCID: PMC7746802 DOI: 10.3389/fmolb.2020.618088] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022] Open
Abstract
The bromodomain-containing protein BRD4 has been thought to transmit epigenetic information across cell divisions by binding to both mitotic chromosomes and interphase chromatin. UV-released BRD4 mediates the recruitment of active P-TEFb to the promoter, which enhances transcriptional elongation. However, the dynamic associations between BRD4 and P-TEFb and BRD4-mediated gene regulation after UV stress are largely unknown. In this study, we found that BRD4 dissociates from chromatin within 30 min after UV treatment and thereafter recruits chromatin. However, P-TEFb binds tightly to chromatin right after UV treatment, suggesting that no interactions occur between BRD4 and P-TEFb within 30 min after UV stress. BRD4 knockdown changes the distribution of P-TEFb among nuclear soluble and chromatin and downregulates the elongation activity of RNA polymerase II. Inhibition of JNK kinase but not other MAP kinases impedes the interactions between BRD4 and P-TEFb. RNA-seq and ChIP assays indicate that BRD4 both positively and negatively regulates gene transcription in cells treated with UV stress. These results reveal previously unrecognized dynamics of BRD4 and P-TEFb after UV stress and regulation of gene transcription by BRD4 acting as either activator or repressor in a context-dependent manner.
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Affiliation(s)
- Yawei Song
- School of Life Sciences, University of Science and Technology of China, Hefei, China.,CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China.,Bioland Laboratory (Guangzhou Regenerative Medicine and Health GuangDong Laboratory), Guangzhou, China.,Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Gongcheng Hu
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China.,Bioland Laboratory (Guangzhou Regenerative Medicine and Health GuangDong Laboratory), Guangzhou, China.,Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Jinping Jia
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China
| | - Mingze Yao
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China
| | - Xiaoshan Wang
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China
| | - Wenliang Lu
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China
| | - Andrew P Hutchins
- Department of Biology, Southern University of Science and Technology, Shenzhen, China
| | - Jiekai Chen
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China.,Bioland Laboratory (Guangzhou Regenerative Medicine and Health GuangDong Laboratory), Guangzhou, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Keiko Ozato
- Division of Developmental Biology, National Institute of Child Health and Human Development, Bethesda, MD, United States
| | - Hongjie Yao
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China.,Bioland Laboratory (Guangzhou Regenerative Medicine and Health GuangDong Laboratory), Guangzhou, China.,Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
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Ryan KR, Giles F, Morgan GJ. Targeting both BET and CBP/EP300 proteins with the novel dual inhibitors NEO2734 and NEO1132 leads to anti-tumor activity in multiple myeloma. Eur J Haematol 2020; 106:90-99. [PMID: 32997383 DOI: 10.1111/ejh.13525] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/22/2020] [Accepted: 09/23/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Two promising epigenetic therapeutic targets have emerged for the treatment of hematologic malignancies, BET and CBP/EP300 proteins. Several studies have shown that targeting these individual classes of proteins has anti-tumor activity in multiple myeloma (MM), as well as other cancers. Here, we present the first data exploring the anti-tumor activity of two novel dual inhibitors, NEO2734 and NEO1132, of both BET and CBP/EP300 proteins in MM. METHODS Sixteen MM cell lines (MMCLs) were treated with the dual inhibitors NEO2734 and NEO1132, the single BET inhibitors JQ1, OTX015, IBET-762, and IBET-151, and a single CBP/EP300 inhibitor CPI-637. RESULTS The dual inhibitor NEO2734 showed strong anti-tumor activity and was consistently highly active against all MMCLs, being as potent as JQ1 and more so than other single inhibitors. NEO2734 and NEO11132 induced a significant G1 cell cycle arrest and decreased c-MYC and IRF4 protein levels in MMCLs compared to the other single inhibitors. Sensitivity to the dual inhibitors was not dependent on a specific MM molecular subgroup but correlated with c-MYC protein expression levels. CONCLUSIONS The dual inhibition of BET and CBP/EP300 has potential therapeutic benefits for patients with MM.
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Affiliation(s)
| | - Francis Giles
- Developmental Therapeutics Consortium, Chicago, IL, USA
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47
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Zhang Y, Duan S, Jang A, Mao L, Liu X, Huang G. JQ1, a selective inhibitor of BRD4, suppresses retinoblastoma cell growth by inducing cell cycle arrest and apoptosis. Exp Eye Res 2020; 202:108304. [PMID: 33080301 DOI: 10.1016/j.exer.2020.108304] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 10/02/2020] [Accepted: 10/13/2020] [Indexed: 12/11/2022]
Abstract
Retinoblastoma (RB) is the most common intraocular cancer in children, and chemotherapy has been the first-line treatment. However, due to the side effects of chemotherapy drugs, novel treatments must be developed. JQ1, a selective inhibitor of BRD4, suppresses cell growth in several cancers in which BRD4 is overexpressed. In the present study, BRD4 was overexpressed in retinoblastoma, and JQ1 effectively inhibited RB cell proliferation and colony formation by inducing cell cycle arrest and promoting apoptosis. Furthermore, the Myc-P21-CDK2 and Myc-cyclinD3/CDK6 pathways were activated in RB cells treated with JQ1, and an animal experiment suggested that JQ1 significantly inhibited tumour growth in vivo. In conclusion, JQ1 may be a potential drug treatment for retinoblastoma.
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Affiliation(s)
- Yanyan Zhang
- Department of Ophthalmology, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China; Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China; Medical Department of Graduate School, Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Sujuan Duan
- Department of Ophthalmology, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China; Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Alan Jang
- Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Longbing Mao
- Medical Department of Graduate School, Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Xing Liu
- Medical Department of Graduate School, Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Guofu Huang
- Department of Ophthalmology, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China; Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China.
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Dual inhibitors of histone deacetylases and other cancer-related targets: A pharmacological perspective. Biochem Pharmacol 2020; 182:114224. [PMID: 32956642 DOI: 10.1016/j.bcp.2020.114224] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 09/01/2020] [Accepted: 09/16/2020] [Indexed: 12/14/2022]
Abstract
Epigenetic enzymes histone deacetylases (HDACs) are clinically validated anticancer drug targets which have been studied intensively in the past few decades. Although several drugs have been approved in this field, they are still limited to a subset of hematological malignancies (in particular T-cell lymphomas), with therapeutic potential not fully realized and the drug-resistance occurred after a certain period of use. To maximize the therapeutic potential of these classes of anticancer drugs, and to extend their application to solid tumors, numerous combination therapies containing an HDACi and an anticancer agent from other mechanisms are currently ongoing in clinical trials. Recently, dual targeting strategy comprising the HDACs component has emerged as an alternative approach for combination therapies. In this perspective, we intend to gather all HDACs-containing dual inhibitors related to cancer therapy published in literature since 2015, classify them into five categories based on targets' biological functions, and discuss the rationale why dual acting agents should work better than combinatorial therapies using two separate drugs. The article discusses the pharmacological aspects of these dual inhibitors, including in vitro biological activities, pharmacokinetic studies, in vivo efficacy studies, as well as available clinical trials. The review of the current status and advances should provide better analysis for future opportunities and challenges of this field.
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Bromodomain-containing protein 4 regulates a cascade of lipid-accumulation-related genes at the transcriptional level in the 3T3-L1 white adipocyte-like cell line. Eur J Pharmacol 2020; 883:173351. [PMID: 32650006 DOI: 10.1016/j.ejphar.2020.173351] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 06/05/2020] [Accepted: 07/03/2020] [Indexed: 11/20/2022]
Abstract
Our previous study demonstrated that the transfection of a short hairpin (sh)RNA targeting bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family of proteins, into 3T3-L1 cells, a white adipocyte-like cell line, reduced the expression of insulin sensitivity genes, such as Adipoq, Fabp4, Lpl, Slc2a4 and Dgat1, and that BRD4 directly bound to the Adipoq, Slc2a4 and Lpl genes. In the present study, we aimed to identify other target genes of BRD4 by microarray analysis of Brd4 shRNA- and control shRNA-transfected cells. We found that the expression of many genes related to fat metabolism, and particularly those involved in fat accumulation in the glycolytic pathway, tricarboxylic acid cycle, and triacylglycerol synthesis, such as Dgat2, Gpd1, Acsl1, Pnpla2, Pgkfb3, Pcx, Fasn, Acacb and Cidec, was reduced by Brd4 shRNA transfection 2 and 8 days after the end of adipocyte differentiation. The binding of BRD4 at the 2-day and histone acetylation at the 8-day time point, in the vicinity of the Dgat2, Gpd1, Acsl1 and Cidec genes, was also reduced by Brd4 shRNA transduction. Treatment with low doses (10-100 nM) of the BET family inhibitor (+)-JQ-1 for 2, 4 or 8 days also reduced the expression of Dgat2, Gpd1, Fasn, Acab, Acsl1, Pnpla2 and Cidec in 3T3-L1 white adipocyte-like cells. These results indicate that BRD4 regulates the expression of numerous genes involved in lipid accumulation at the transcriptional level in a white adipocyte-like cell line.
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50
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Wu SL, Wang LF, Sun HB, Wang W, Yu YX. Probing molecular mechanism of inhibitor bindings to bromodomain-containing protein 4 based on molecular dynamics simulations and principal component analysis. SAR AND QSAR IN ENVIRONMENTAL RESEARCH 2020; 31:547-570. [PMID: 32657160 DOI: 10.1080/1062936x.2020.1777584] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 05/31/2020] [Indexed: 06/11/2023]
Abstract
It is well known that bromodomain-containing protein 4 (BRD4) has been thought as a promising target utilized for treating various human diseases, such as inflammatory disorders, malignant tumours, acute myelogenous leukaemia (AML), bone diseases, etc. For this study, molecular dynamics (MD) simulations, binding free energy calculations, and principal component analysis (PCA) were integrated together to uncover binding modes of inhibitors 8P9, 8PU, and 8PX to BRD4(1). The results obtained from binding free energy calculations show that van der Waals interactions act as the main regulator in bindings of inhibitors to BRD4(1). The information stemming from PCA reveals that inhibitor associations extremely affect conformational changes, internal dynamics, and movement patterns of BRD4(1). Residue-based free energy decomposition method was wielded to unveil contributions of independent residues to inhibitor bindings and the data signify that hydrogen bonding interactions and hydrophobic interactions are decisive factors affecting bindings of inhibitors to BRD4(1). Meanwhile, eight residues Trp81, Pro82, Val87, Leu92, Leu94, Cys136, Asn140, and Ile146 are recognized as the common hot interaction spots of three inhibitors with BRD4(1). The results from this work are expected to provide a meaningfully theoretical guidance for design and development of effective inhibitors inhibiting of the activity of BRD4.
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Affiliation(s)
- S L Wu
- School of Science, Shandong Jiaotong University , Jinan, China
| | - L F Wang
- School of Science, Shandong Jiaotong University , Jinan, China
| | - H B Sun
- School of Science, Shandong Jiaotong University , Jinan, China
| | - W Wang
- School of Science, Shandong Jiaotong University , Jinan, China
| | - Y X Yu
- School of Science, Shandong Jiaotong University , Jinan, China
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