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 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

doi:10.1038/s41467-022-30257-z

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

Urology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	2559
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30257-z
State	Published - Dec 2022

ASJC Scopus subject areas

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

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Qiu, X., Boufaied, N., Hallal, T., Feit, A., de Polo, A., Luoma, A. M., Alahmadi, W., Larocque, J., Zadra, G., Xie, Y., Gu, S., Tang, Q., Zhang, Y., Syamala, S., Seo, J. H., Bell, C., O’Connor, E., Liu, Y., Schaeffer, E. M., ... Labbé, D. P. (2022). MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets. Nature communications, 13(1), Article 2559. https://doi.org/10.1038/s41467-022-30257-z

Qiu, X, Boufaied, N, Hallal, T, Feit, A, de Polo, A, Luoma, AM, Alahmadi, W, Larocque, J, Zadra, G, Xie, Y, Gu, S, Tang, Q, Zhang, Y, Syamala, S, Seo, JH, Bell, C, O’Connor, E, Liu, Y, Schaeffer, EM, Jeffrey Karnes, R, Weinmann, S, Davicioni, E, Morrissey, C, Cejas, P, Ellis, L, Loda, M, Wucherpfennig, KW, Pomerantz, MM, Spratt, DE, Corey, E, Freedman, ML, Shirley Liu, X, Brown, M, Long, HW & Labbé, DP 2022, 'MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets', Nature communications, vol. 13, no. 1, 2559. https://doi.org/10.1038/s41467-022-30257-z

@article{1164d1181e3342abb90836f116f56b11,

title = "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. 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.",

author = "Xintao Qiu and Nadia Boufaied and Tarek Hallal and Avery Feit and {de Polo}, Anna and Luoma, {Adrienne M.} and Walaa Alahmadi and Janie Larocque and Giorgia Zadra and Yingtian Xie and Shengqing Gu and Qin Tang and Yi Zhang and Sudeepa Syamala and Seo, {Ji Heui} and Connor Bell and Edward O{\textquoteright}Connor and Yang Liu and Schaeffer, {Edward M.} and {Jeffrey Karnes}, R. and Sheila Weinmann and Elai Davicioni and Colm Morrissey and Paloma Cejas and Leigh Ellis and Massimo Loda and Wucherpfennig, {Kai W.} and Pomerantz, {Mark M.} and Spratt, {Daniel E.} and Eva Corey and Freedman, {Matthew L.} and {Shirley Liu}, X. and Myles Brown and Long, {Henry W.} and Labb{\'e}, {David P.}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-30257-z",

language = "English (US)",

volume = "13",

journal = "Nature communications",

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T1 - MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets

AU - Qiu, Xintao

AU - Boufaied, Nadia

AU - Hallal, Tarek

AU - Feit, Avery

AU - de Polo, Anna

AU - Luoma, Adrienne M.

AU - Alahmadi, Walaa

AU - Larocque, Janie

AU - Zadra, Giorgia

AU - Xie, Yingtian

AU - Gu, Shengqing

AU - Tang, Qin

AU - Zhang, Yi

AU - Syamala, Sudeepa

AU - Seo, Ji Heui

AU - Bell, Connor

AU - O’Connor, Edward

AU - Liu, Yang

AU - Schaeffer, Edward M.

AU - Jeffrey Karnes, R.

AU - Weinmann, Sheila

AU - Davicioni, Elai

AU - Morrissey, Colm

AU - Cejas, Paloma

AU - Ellis, Leigh

AU - Loda, Massimo

AU - Wucherpfennig, Kai W.

AU - Pomerantz, Mark M.

AU - Spratt, Daniel E.

AU - Corey, Eva

AU - Freedman, Matthew L.

AU - Shirley Liu, X.

AU - Brown, Myles

AU - Long, Henry W.

AU - Labbé, David P.

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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ER -

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

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