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

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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10.1038/s41467-022-30257-z

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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), [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 = "Funding Information: R.J.K. receive royalties from GenomeDx (now Veracyte) for Decipher testing. S.W. receives research funding from PreludeDX. K.W.W. serves on the scientific advisory board of T-Scan Therapeutics, SQZ Biotech, Nextechinvest and receives sponsored research funding from Novartis. He is a co-founder of Immunitas, a biotech company. These activities are not related to the research reported in this publication. D.E.S. receives personal fees from Janssen, AstraZeneca, and Blue Earth and funding from Janssen. E.C. received research funding under institutional SRA from Janssen Research and Development, Bayer Pharmaceuticals, KronosBio, Forma Pharmaceutics, Foghorn, Gilead, Sanofi, AbbVie, MacroGenics, and GSK. M.L.F. reports other support from Nuscan Diagnostics outside the submitted work. X.S.L. conducted the work while being a faculty at the Dana-Farber Cancer Institute and is currently a board member and CEO of GV20. M.B. and H.W.L. receives sponsored research support from Novartis. M.B. is a consultant to Aleta Biotherapeutics and H3 Biomedicine and serves on the SAB of Kronos Bio. The remaining authors declare no competing interests. Funding Information: We thank Zach Herbert for technical assistance, Noriko Uetani for Figs. , and design and drawings and Marie-Claude Gingras and Livia Garzia for critical review of this manuscript. T.H. is the recipient of the 100 Days Across Canada Bursary Award. J.L. is a recipient of a Canadian Institute of Health Research Frederick Banting and Charles Best Canada Graduate Scholarship-Master{\textquoteright}s and of a Research Institute of the McGill University Health Centre M.Sc. Studentship award. Establishment and characterization of the LuCaP PDX models has been supported by the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the U.S. Department of Defense Prostate Cancer Biorepository Network (W81XWH-14-2-0183), the Prostate Cancer Foundation, the Institute for Prostate Cancer Research, and the Richard M. Lucas Foundation. We would like to thank the patients who generously donated tissue that made this research possible. G.Z. is a recipient of an Idea Development Award from the U.S. Department of Defense (PC150263) and the Barr Award from the Dana-Farber Cancer Institute. This work has been supported by National Institutes of Health grants to K.W.W. (R01 CA238039; R01 CA251599), a Prostate Cancer Foundation Challenge Award to M.M.P. and M.L.F. and grants to M.L.F. (National Institutes of Health, R01 GM107427, R01 CA251555 and R01 CA193910; U.S. Department of Defense, W81XWH-19-1-0565 and W81XWH-21-1-0234; the H.L. Snyder Medical Research Foundation; the Donahue Family Fund; the Mayer Foundation; the Cutler Family Fund for Prevention and Early Detection; the Claudia Adams Barr Program for Innovative Cancer Research). E.C., M.B. and H.W.L. acknowledge support from the National Institutes of Health (P01 CA163227-06A1). D.P.L. is a William Dawson Scholar of McGill University, a Lewis Katz – Young Investigator of the Prostate Cancer Foundation, the recipient of a Scholarship for the Next Generation of Scientists from the Cancer Research Society and is also a Research Scholar – Junior 1 from The Fonds de Recherche du Qu{\'e}bec – Sant{\'e}. The work reported here was funded by a Canadian Institutes of Health Research project grant (PJT-162246) to D.P.L. Funding Information: We thank Zach Herbert for technical assistance, Noriko Uetani for Figs. 1a , 3f and 8b design and drawings and Marie-Claude Gingras and Livia Garzia for critical review of this manuscript. T.H. is the recipient of the 100 Days Across Canada Bursary Award. J.L. is a recipient of a Canadian Institute of Health Research Frederick Banting and Charles Best Canada Graduate Scholarship-Master{\textquoteright}s and of a Research Institute of the McGill University Health Centre M.Sc. Studentship award. Establishment and characterization of the LuCaP PDX models has been supported by the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the U.S. Department of Defense Prostate Cancer Biorepository Network (W81XWH-14-2-0183), the Prostate Cancer Foundation, the Institute for Prostate Cancer Research, and the Richard M. Lucas Foundation. We would like to thank the patients who generously donated tissue that made this research possible. G.Z. is a recipient of an Idea Development Award from the U.S. Department of Defense (PC150263) and the Barr Award from the Dana-Farber Cancer Institute. This work has been supported by National Institutes of Health grants to K.W.W. (R01 CA238039; R01 CA251599), a Prostate Cancer Foundation Challenge Award to M.M.P. and M.L.F. and grants to M.L.F. (National Institutes of Health, R01 GM107427, R01 CA251555 and R01 CA193910; U.S. Department of Defense, W81XWH-19-1-0565 and W81XWH-21-1-0234; the H.L. Snyder Medical Research Foundation; the Donahue Family Fund; the Mayer Foundation; the Cutler Family Fund for Prevention and Early Detection; the Claudia Adams Barr Program for Innovative Cancer Research). E.C., M.B. and H.W.L. acknowledge support from the National Institutes of Health (P01 CA163227-06A1). D.P.L. is a William Dawson Scholar of McGill University, a Lewis Katz – Young Investigator of the Prostate Cancer Foundation, the recipient of a Scholarship for the Next Generation of Scientists from the Cancer Research Society and is also a Research Scholar – Junior 1 from The Fonds de Recherche du Qu{\'e}bec – Sant{\'e}. The work reported here was funded by a Canadian Institutes of Health Research project grant (PJT-162246) to D.P.L. 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",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

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.

N1 - Funding Information: R.J.K. receive royalties from GenomeDx (now Veracyte) for Decipher testing. S.W. receives research funding from PreludeDX. K.W.W. serves on the scientific advisory board of T-Scan Therapeutics, SQZ Biotech, Nextechinvest and receives sponsored research funding from Novartis. He is a co-founder of Immunitas, a biotech company. These activities are not related to the research reported in this publication. D.E.S. receives personal fees from Janssen, AstraZeneca, and Blue Earth and funding from Janssen. E.C. received research funding under institutional SRA from Janssen Research and Development, Bayer Pharmaceuticals, KronosBio, Forma Pharmaceutics, Foghorn, Gilead, Sanofi, AbbVie, MacroGenics, and GSK. M.L.F. reports other support from Nuscan Diagnostics outside the submitted work. X.S.L. conducted the work while being a faculty at the Dana-Farber Cancer Institute and is currently a board member and CEO of GV20. M.B. and H.W.L. receives sponsored research support from Novartis. M.B. is a consultant to Aleta Biotherapeutics and H3 Biomedicine and serves on the SAB of Kronos Bio. The remaining authors declare no competing interests. Funding Information: We thank Zach Herbert for technical assistance, Noriko Uetani for Figs. , and design and drawings and Marie-Claude Gingras and Livia Garzia for critical review of this manuscript. T.H. is the recipient of the 100 Days Across Canada Bursary Award. J.L. is a recipient of a Canadian Institute of Health Research Frederick Banting and Charles Best Canada Graduate Scholarship-Master’s and of a Research Institute of the McGill University Health Centre M.Sc. Studentship award. Establishment and characterization of the LuCaP PDX models has been supported by the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the U.S. Department of Defense Prostate Cancer Biorepository Network (W81XWH-14-2-0183), the Prostate Cancer Foundation, the Institute for Prostate Cancer Research, and the Richard M. Lucas Foundation. We would like to thank the patients who generously donated tissue that made this research possible. G.Z. is a recipient of an Idea Development Award from the U.S. Department of Defense (PC150263) and the Barr Award from the Dana-Farber Cancer Institute. This work has been supported by National Institutes of Health grants to K.W.W. (R01 CA238039; R01 CA251599), a Prostate Cancer Foundation Challenge Award to M.M.P. and M.L.F. and grants to M.L.F. (National Institutes of Health, R01 GM107427, R01 CA251555 and R01 CA193910; U.S. Department of Defense, W81XWH-19-1-0565 and W81XWH-21-1-0234; the H.L. Snyder Medical Research Foundation; the Donahue Family Fund; the Mayer Foundation; the Cutler Family Fund for Prevention and Early Detection; the Claudia Adams Barr Program for Innovative Cancer Research). E.C., M.B. and H.W.L. acknowledge support from the National Institutes of Health (P01 CA163227-06A1). D.P.L. is a William Dawson Scholar of McGill University, a Lewis Katz – Young Investigator of the Prostate Cancer Foundation, the recipient of a Scholarship for the Next Generation of Scientists from the Cancer Research Society and is also a Research Scholar – Junior 1 from The Fonds de Recherche du Québec – Santé. The work reported here was funded by a Canadian Institutes of Health Research project grant (PJT-162246) to D.P.L. Funding Information: We thank Zach Herbert for technical assistance, Noriko Uetani for Figs. 1a , 3f and 8b design and drawings and Marie-Claude Gingras and Livia Garzia for critical review of this manuscript. T.H. is the recipient of the 100 Days Across Canada Bursary Award. J.L. is a recipient of a Canadian Institute of Health Research Frederick Banting and Charles Best Canada Graduate Scholarship-Master’s and of a Research Institute of the McGill University Health Centre M.Sc. Studentship award. Establishment and characterization of the LuCaP PDX models has been supported by the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the U.S. Department of Defense Prostate Cancer Biorepository Network (W81XWH-14-2-0183), the Prostate Cancer Foundation, the Institute for Prostate Cancer Research, and the Richard M. Lucas Foundation. We would like to thank the patients who generously donated tissue that made this research possible. G.Z. is a recipient of an Idea Development Award from the U.S. Department of Defense (PC150263) and the Barr Award from the Dana-Farber Cancer Institute. This work has been supported by National Institutes of Health grants to K.W.W. (R01 CA238039; R01 CA251599), a Prostate Cancer Foundation Challenge Award to M.M.P. and M.L.F. and grants to M.L.F. (National Institutes of Health, R01 GM107427, R01 CA251555 and R01 CA193910; U.S. Department of Defense, W81XWH-19-1-0565 and W81XWH-21-1-0234; the H.L. Snyder Medical Research Foundation; the Donahue Family Fund; the Mayer Foundation; the Cutler Family Fund for Prevention and Early Detection; the Claudia Adams Barr Program for Innovative Cancer Research). E.C., M.B. and H.W.L. acknowledge support from the National Institutes of Health (P01 CA163227-06A1). D.P.L. is a William Dawson Scholar of McGill University, a Lewis Katz – Young Investigator of the Prostate Cancer Foundation, the recipient of a Scholarship for the Next Generation of Scientists from the Cancer Research Society and is also a Research Scholar – Junior 1 from The Fonds de Recherche du Québec – Santé. The work reported here was funded by a Canadian Institutes of Health Research project grant (PJT-162246) to D.P.L. Publisher Copyright: © 2022, The Author(s).

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.

UR - http://www.scopus.com/inward/record.url?scp=85130021714&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85130021714&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-30257-z

DO - 10.1038/s41467-022-30257-z

M3 - Article

C2 - 35562350

AN - SCOPUS:85130021714

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2559

ER -

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

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