MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets
MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets
ABSTRACT c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Importantly, analyses of clinical specimens revealed that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq revealed an increased RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes. STATEMENT OF SIGNIFICANCEAR and MYC are key to prostate cancer etiology but our current understanding of their interplay is scarce. Here we show that the oncogenic transcription factor MYC can pause the transcriptional program of the master transcription factor in prostate cancer, AR, while turning on its own, even more lethal program.
Qiu Xintao、Liu Yang、Schaeffer Edward M.、Karnes R. Jeffrey、Brown Myles、Boufaied Nadia、Hallal Tarek、de Polo Anna、Luoma Adrienne M.、Zadra Giorgia、Zhang Yi、Syamala Sudeepa、Seo Ji-Heui、Bell Connor、Liu X. Shirley、Spratt Daniel E.、Feit Avery、Cejas Paloma、O?ˉConnor Edward、Weinmann Sheila、Tang Qin、Corey Eva、Labb¨| David P.、Ellis Leigh、Larocque Janie、Loda Massimo、Xie Yingtian、Wucherpfennig Kai W.、Davicioni Elai、Pomerantz Mark M.、Freedman Matthew L.、Long Henry W.、Gu Shengqing
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute||Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDecipher BiosciencesDepartment of Urology, Northwestern UniversityDepartment of Urology, Mayo Clinic, RochesterCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute||Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolCancer Research Program, Research Institute of the McGill University Health CentreCancer Research Program, Research Institute of the McGill University Health Centre||Department of Anatomy and Cell Biology, McGill UniversityCancer Research Program, Research Institute of the McGill University Health Centre||Division of Urology, Department of Surgery, McGill UniversityDepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartments of Oncologic Pathology and Pathology, Dana-Farber Cancer Institute and Brigham?ˉs Women Hospital||Institute of Molecular Genetics, Research National CouncilCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute||Department of Data Science, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public HealthCenter for Functional Cancer Epigenetics, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute||Department of Data Science, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public HealthDepartment of Radiation Oncology, University of MichiganCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute||Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute||Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolCenter for Health Research, Kaiser Permanente NorthwestCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute||Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School||Department of Data Science, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public HealthDepartment of Urology, University of WashingtonCancer Research Program, Research Institute of the McGill University Health Centre||Department of Anatomy and Cell Biology, McGill University||Division of Urology, Department of Surgery, McGill University||Division of Experimental Medicine, Department of Medicine, McGill UniversityDivision of Medical Oncology, Department of Medicine, Cedars-Sinai Medical Center and Cedars-Sinai Samual Oschin Comprehensive Cancer InstituteCancer Research Program, Research Institute of the McGill University Health Centre||Division of Experimental Medicine, Department of Medicine, McGill UniversityDepartment of Pathology and Laboratory Medicine, Weil Cornell Medicine, New York Presbyterian-Weill Cornell CampusCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute||Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical SchoolDecipher BiosciencesDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute||Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School||The Eli and Edythe L. Broad InstituteCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute||Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute||Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School||Department of Data Science, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health
肿瘤学基础医学分子生物学
Qiu Xintao,Liu Yang,Schaeffer Edward M.,Karnes R. Jeffrey,Brown Myles,Boufaied Nadia,Hallal Tarek,de Polo Anna,Luoma Adrienne M.,Zadra Giorgia,Zhang Yi,Syamala Sudeepa,Seo Ji-Heui,Bell Connor,Liu X. Shirley,Spratt Daniel E.,Feit Avery,Cejas Paloma,O?ˉConnor Edward,Weinmann Sheila,Tang Qin,Corey Eva,Labb¨| David P.,Ellis Leigh,Larocque Janie,Loda Massimo,Xie Yingtian,Wucherpfennig Kai W.,Davicioni Elai,Pomerantz Mark M.,Freedman Matthew L.,Long Henry W.,Gu Shengqing.MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets[EB/OL].(2025-03-28)[2025-04-29].https://www.biorxiv.org/content/10.1101/2021.04.23.441016.点此复制
评论