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

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 KarnesSheila 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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number2559
JournalNature communications
Issue number1
StatePublished - Dec 2022

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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