IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-30257-z.html
   My bibliography  Save this article

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

Author

Listed:
  • Xintao Qiu

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute, Harvard Medical School)

  • Nadia Boufaied

    (Research Institute of the McGill University Health Centre)

  • Tarek Hallal

    (Research Institute of the McGill University Health Centre
    McGill University)

  • Avery Feit

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute, Harvard Medical School)

  • Anna Polo

    (Research Institute of the McGill University Health Centre
    McGill University)

  • Adrienne M. Luoma

    (Harvard Medical School)

  • Walaa Alahmadi

    (Research Institute of the McGill University Health Centre
    McGill University)

  • Janie Larocque

    (Research Institute of the McGill University Health Centre
    McGill University)

  • Giorgia Zadra

    (Dana-Farber Cancer Institute and Brigham’s Women Hospital
    National Research Council)

  • Yingtian Xie

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute, Harvard Medical School)

  • Shengqing Gu

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute, Harvard Medical School
    Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health)

  • Qin Tang

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute, Harvard Medical School
    Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health)

  • Yi Zhang

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health)

  • 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
    Dana-Farber Cancer Institute, Harvard Medical School)

  • Leigh Ellis

    (Cedars-Sinai Medical Center
    Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute
    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
    Dana-Farber Cancer Institute, Harvard Medical School
    The Eli and Edythe L. Broad Institute)

  • X. Shirley Liu

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health)

  • Myles Brown

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute, Harvard Medical School)

  • Henry W. Long

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute, Harvard Medical School)

  • David P. Labbé

    (Research Institute of the McGill University Health Centre
    McGill University
    McGill University
    McGill University)

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.

Suggested Citation

  • 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 , 2022. "MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30257-z
    DOI: 10.1038/s41467-022-30257-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-30257-z
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-30257-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Jason Ernst & Pouya Kheradpour & Tarjei S. Mikkelsen & Noam Shoresh & Lucas D. Ward & Charles B. Epstein & Xiaolan Zhang & Li Wang & Robbyn Issner & Michael Coyne & Manching Ku & Timothy Durham & Mano, 2011. "Mapping and analysis of chromatin state dynamics in nine human cell types," Nature, Nature, vol. 473(7345), pages 43-49, May.
    2. Marco Matejcic & Edward J. Saunders & Tokhir Dadaev & Mark N. Brook & Kan Wang & Xin Sheng & Ali Amin Al Olama & Fredrick R. Schumacher & Sue A. Ingles & Koveela Govindasami & Sara Benlloch & Sonja I., 2018. "Germline variation at 8q24 and prostate cancer risk in men of European ancestry," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Sukanya Panja & Mihai Ioan Truica & Christina Y. Yu & Vamshi Saggurthi & Michael W. Craige & Katie Whitehead & Mayra V. Tuiche & Aymen Al-Saadi & Riddhi Vyas & Shridar Ganesan & Suril Gohel & Frederic, 2024. "Mechanism-centric regulatory network identifies NME2 and MYC programs as markers of Enzalutamide resistance in CRPC," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    2. Mindy K. Graham & Rulin Wang & Roshan Chikarmane & Bulouere Abel & Ajay Vaghasia & Anuj Gupta & Qizhi Zheng & Jessica Hicks & Polina Sysa-Shah & Xin Pan & Nicole Castagna & Jianyong Liu & Jennifer Mey, 2024. "Convergent alterations in the tumor microenvironment of MYC-driven human and murine prostate cancer," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Seungsoo Hahn & Dongsup Kim, 2015. "Identifying and Reducing Systematic Errors in Chromosome Conformation Capture Data," PLOS ONE, Public Library of Science, vol. 10(12), pages 1-17, December.
    2. Ye Cai & Huifen Cao & Fang Wang & Yufei Zhang & Philipp Kapranov, 2022. "Complex genomic patterns of abasic sites in mammalian DNA revealed by a high-resolution SSiNGLe-AP method," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    3. Chirag Nepal & Jesper B. Andersen, 2023. "Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Haoxi Chai & Harianto Tjong & Peng Li & Wei Liao & Ping Wang & Chee Hong Wong & Chew Yee Ngan & Warren J. Leonard & Chia-Lin Wei & Yijun Ruan, 2023. "ChIATAC is an efficient strategy for multi-omics mapping of 3D epigenomes from low-cell inputs," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Zhangyuan Pan & Yuelin Yao & Hongwei Yin & Zexi Cai & Ying Wang & Lijing Bai & Colin Kern & Michelle Halstead & Ganrea Chanthavixay & Nares Trakooljul & Klaus Wimmers & Goutam Sahana & Guosheng Su & M, 2021. "Pig genome functional annotation enhances the biological interpretation of complex traits and human disease," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    6. Maurizio Mangolini & Alba Maiques-Diaz & Stella Charalampopoulou & Elena Gerhard-Hartmann & Johannes Bloehdorn & Andrew Moore & Giorgia Giachetti & Junyan Lu & Valar Nila Roamio Franklin & Chandra Sek, 2022. "Viral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    7. Carlos Rivera & Hun-Goo Lee & Anna Lappala & Danni Wang & Verónica Noches & Montserrat Olivares-Costa & Marcela Sjöberg-Herrera & Jeannie T. Lee & María Estela Andrés, 2022. "Unveiling RCOR1 as a rheostat at transcriptionally permissive chromatin," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Noah Dukler & Mehreen R. Mughal & Ritika Ramani & Yi-Fei Huang & Adam Siepel, 2022. "Extreme purifying selection against point mutations in the human genome," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    9. Ting Shen & Ting Ni & Jiaxuan Chen & Haitao Chen & Xiaopin Ma & Guangwen Cao & Tianzhi Wu & Haisheng Xie & Bin Zhou & Gang Wei & Hexige Saiyin & Suqin Shen & Peng Yu & Qianyi Xiao & Hui Liu & Yuzheng , 2022. "An enhancer variant at 16q22.1 predisposes to hepatocellular carcinoma via regulating PRMT7 expression," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    10. Julia Truch & Damien J. Downes & Caroline Scott & E. Ravza Gür & Jelena M. Telenius & Emmanouela Repapi & Ron Schwessinger & Matthew Gosden & Jill M. Brown & Stephen Taylor & Pak Leng Cheong & Jim R. , 2022. "The chromatin remodeller ATRX facilitates diverse nuclear processes, in a stochastic manner, in both heterochromatin and euchromatin," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    11. Rachel K. Lex & Weiqiang Zhou & Zhicheng Ji & Kristin N. Falkenstein & Kaleigh E. Schuler & Kathryn E. Windsor & Joseph D. Kim & Hongkai Ji & Steven A. Vokes, 2022. "GLI transcriptional repression is inert prior to Hedgehog pathway activation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    12. Zhaoyun Ding & Ting Cai & Jupei Tang & Hanxiao Sun & Xinyi Qi & Yunpeng Zhang & Yan Ji & Liyun Yuan & Huidan Chang & Yanhui Ma & Hong Zhou & Li Li & Huiming Sheng & Ju Qiu, 2022. "Setd2 supports GATA3+ST2+ thymic-derived Treg cells and suppresses intestinal inflammation," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    13. Jennifer P. Nguyen & Timothy D. Arthur & Kyohei Fujita & Bianca M. Salgado & Margaret K. R. Donovan & Hiroko Matsui & Ji Hyun Kim & Agnieszka D’Antonio-Chronowska & Matteo D’Antonio & Kelly A. Frazer, 2023. "eQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    14. Carlos Olmeda-Gómez & Carlos Romá-Mateo & Maria-Antonia Ovalle-Perandones, 2019. "Overview of trends in global epigenetic research (2009–2017)," Scientometrics, Springer;Akadémiai Kiadó, vol. 119(3), pages 1545-1574, June.
    15. Chaitali Chakraborty & Itzel Nissen & Craig A. Vincent & Anna-Carin Hägglund & Andreas Hörnblad & Silvia Remeseiro, 2023. "Rewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    16. Mujahid Ali & Lubna Younas & Jing Liu & Huangyi He & Xinpei Zhang & Qi Zhou, 2024. "Development and evolution of Drosophila chromatin landscape in a 3D genome context," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    17. Mijeong Kim & Shili Lin, 2020. "Characterization of histone modification patterns and prediction of novel promoters using functional principal component analysis," PLOS ONE, Public Library of Science, vol. 15(5), pages 1-16, May.
    18. M S Vijayabaskar & Debbie K Goode & Nadine Obier & Monika Lichtinger & Amber M L Emmett & Fatin N Zainul Abidin & Nisar Shar & Rebecca Hannah & Salam A Assi & Michael Lie-A-Ling & Berthold Gottgens & , 2019. "Identification of gene specific cis-regulatory elements during differentiation of mouse embryonic stem cells: An integrative approach using high-throughput datasets," PLOS Computational Biology, Public Library of Science, vol. 15(11), pages 1-29, November.
    19. Mary F Feitosa & Aldi T Kraja & Daniel I Chasman & Yun J Sung & Thomas W Winkler & Ioanna Ntalla & Xiuqing Guo & Nora Franceschini & Ching-Yu Cheng & Xueling Sim & Dina Vojinovic & Jonathan Marten & S, 2018. "Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries," PLOS ONE, Public Library of Science, vol. 13(6), pages 1-36, June.
    20. Balvert, Marleen, 2018. "An image representation based convolutional network for DNA classification," Other publications TiSEM ad842137-1a50-444a-9074-c, Tilburg University, School of Economics and Management.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30257-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.