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. Analyses of clinical specimens reveal 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 uncover an increase in 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.
Nature communications. 2022 May 13*** epublish ***
Xintao Qiu, Nadia Boufaied, Tarek Hallal, Avery Feit, Anna de Polo, Adrienne M Luoma, Walaa Alahmadi, Janie Larocque, Giorgia Zadra, Yingtian Xie, Shengqing Gu, Qin Tang, Yi Zhang, Sudeepa Syamala, Ji-Heui Seo, Connor Bell, Edward O'Connor, Yang Liu, Edward M Schaeffer, R Jeffrey Karnes, Sheila Weinmann, Elai Davicioni, Colm Morrissey, Paloma Cejas, Leigh Ellis, Massimo Loda, Kai W Wucherpfennig, Mark M Pomerantz, Daniel E Spratt, Eva Corey, Matthew L Freedman, X Shirley Liu, Myles Brown, Henry W Long, David P Labbé
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA., Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada., Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Departments of Oncologic Pathology and Pathology, Dana-Farber Cancer Institute and Brigham's Women Hospital, Boston, MA, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Decipher Biosciences, San Diego, CA, USA., Department of Urology, Northwestern University, Chicago, IL, USA., Department of Urology, Mayo Clinic, Rochester, MN, USA., Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA., Department of Urology, University of Washington, Seattle, WA, USA., Division of Medical Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Department of Pathology and Laboratory Medicine, Weil Cornell Medicine, New York Presbyterian-Weill Cornell Campus, New York, NY, USA., Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA., Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. ., Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada. .