MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets
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Published:2022-05-13
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Qiu XintaoORCID, Boufaied Nadia, Hallal Tarek, Feit AveryORCID, de Polo Anna, Luoma Adrienne M.ORCID, Alahmadi Walaa, Larocque Janie, Zadra Giorgia, Xie Yingtian, Gu Shengqing, Tang Qin, Zhang YiORCID, Syamala SudeepaORCID, Seo Ji-Heui, Bell Connor, O’Connor Edward, Liu Yang, Schaeffer Edward M.ORCID, Jeffrey Karnes R., Weinmann Sheila, Davicioni Elai, Morrissey Colm, Cejas PalomaORCID, Ellis LeighORCID, Loda MassimoORCID, Wucherpfennig Kai W.ORCID, Pomerantz Mark M., Spratt Daniel E.ORCID, Corey EvaORCID, Freedman Matthew L., Shirley Liu X.ORCID, Brown MylesORCID, Long Henry W.ORCID, Labbé David P.ORCID
Abstract
Abstractc-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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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