MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets

Xintao Qiu, Nadia Boufaied, Tarek Hallal, Avery Feit, Anna 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 () and David P. Labbé ()
Additional contact information
Xintao Qiu: Dana-Farber Cancer Institute
Nadia Boufaied: Research Institute of the McGill University Health Centre
Tarek Hallal: Research Institute of the McGill University Health Centre
Avery Feit: Dana-Farber Cancer Institute
Anna Polo: Research Institute of the McGill University Health Centre
Adrienne M. Luoma: Harvard Medical School
Walaa Alahmadi: Research Institute of the McGill University Health Centre
Janie Larocque: Research Institute of the McGill University Health Centre
Giorgia Zadra: Dana-Farber Cancer Institute and Brigham’s Women Hospital
Yingtian Xie: Dana-Farber Cancer Institute
Shengqing Gu: Dana-Farber Cancer Institute
Qin Tang: Dana-Farber Cancer Institute
Yi Zhang: Dana-Farber Cancer Institute
Sudeepa Syamala: Dana-Farber Cancer Institute
Ji-Heui Seo: Dana-Farber Cancer Institute, Harvard Medical School
Connor Bell: Dana-Farber Cancer Institute, Harvard Medical School
Edward O’Connor: Dana-Farber Cancer Institute, Harvard Medical School
Yang Liu: Decipher Biosciences
Edward M. Schaeffer: Northwestern University
R. Jeffrey Karnes: Mayo Clinic
Sheila Weinmann: Kaiser Permanente Northwest
Elai Davicioni: Decipher Biosciences
Colm Morrissey: University of Washington
Paloma Cejas: Dana-Farber Cancer Institute
Leigh Ellis: Cedars-Sinai Medical Center
Massimo Loda: Weil Cornell Medicine, New York Presbyterian-Weill Cornell Campus
Kai W. Wucherpfennig: Harvard Medical School
Mark M. Pomerantz: Dana-Farber Cancer Institute, Harvard Medical School
Daniel E. Spratt: University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine
Eva Corey: University of Washington
Matthew L. Freedman: Dana-Farber Cancer Institute
X. Shirley Liu: Dana-Farber Cancer Institute
Myles Brown: Dana-Farber Cancer Institute
Henry W. Long: Dana-Farber Cancer Institute
David P. Labbé: Research Institute of the McGill University Health Centre

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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. 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.

Date: 2022
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DOI: 10.1038/s41467-022-30257-z

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