1. Cancer Biology
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A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer

Research Article
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Cite this article as: eLife 2017;6:e28482 doi: 10.7554/eLife.28482

Abstract

Standard treatment for metastatic prostate cancer (CaP) prevents ligand-activation of androgen receptor (AR). Despite initial remission, CaP progresses while relying on AR. AR transcriptional output controls CaP behavior and is an alternative therapeutic target, but its molecular regulation is poorly understood. Here, we show that action of activated AR partitions into fractions that are controlled preferentially by different coregulators. In a 452-AR-target gene panel, each of 18 clinically relevant coregulators mediates androgen-responsiveness of 0%-57% genes and acts as a coactivator or corepressor in a gene-specific manner. Selectivity in coregulator-dependent AR action is reflected in differential AR binding site composition and involvement with CaP biology and progression. Isolation of a novel transcriptional mechanism in which WDR77 unites the actions of AR and p53, the major genomic drivers of lethal CaP, to control cell cycle progression provides proof-of-principle for treatment via selective interference with AR action by exploiting AR dependence on coregulators.

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Article and author information

Author details

  1. Song Liu

    Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Sangeeta Kumari

    Department of Cancer Biology, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Qiang Hu

    Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Dhirodatta Senapati

    Department of Cancer Biology, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Varadha Balaji Venkadakrishnan

    Department of Cancer Biology, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Dan Wang

    Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Adam D DePriest

    Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Simon E Schlanger

    Department of Cancer Biology, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Salma Ben-Salem

    Department of Cancer Biology, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Malyn May Valenzuela

    Department of Cancer Biology, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Belinda Willard

    Research Core Services, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Shaila Mudambi

    Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Wendy M Swetzig

    Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Gokul M Das

    Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Mojgan Shourideh

    Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Shahriah Koochekpour

    Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Sara Moscovita Falzarano

    Department of Anatomic Pathology, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Cristina Magi-Galluzzi

    Department of Anatomic Pathology, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Neelu Yadav

    Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Xiwei Chen

    Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Changshi Lao

    Institute of Nanosurface Science and Engineering, Shenzhen University, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  22. Jianmin Wang

    Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  23. Jean-Noel Billaud

    QIAGEN Bioinformatics, Redwood City, United States
    Competing interests
    The authors declare that no competing interests exist.
  24. Hannelore Heemers

    Department of Cancer Biology, Cleveland Clinic, Cleveland, United States
    For correspondence
    heemerh@ccf.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9137-5083

Funding

Prostate Cancer Foundation

  • Hannelore Heemers

National Cancer Institute (CA166440)

  • Hannelore Heemers

Velosano3

  • Hannelore Heemers

National Cancer Institute (1S10RR031537-01)

  • Belinda Willard

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Maureen Murphy, The Wistar Institute, United States

Publication history

  1. Received: May 9, 2017
  2. Accepted: August 17, 2017
  3. Accepted Manuscript published: August 18, 2017 (version 1)
  4. Version of Record published: September 21, 2017 (version 2)
  5. Version of Record updated: November 22, 2017 (version 3)

Copyright

© 2017, Liu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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Further reading

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    Cell cycle gene expression programs fuel proliferation and are universally dysregulated in cancer. The retinoblastoma (RB)-family of proteins, RB1, RBL1/p107 and RBL2/p130, coordinately repress cell cycle gene expression, inhibiting proliferation and suppressing tumorigenesis. Phosphorylation of RB-family proteins by cyclin dependent kinases is firmly established. Like phosphorylation, ubiquitination is essential to cell cycle control, and numerous proliferative regulators, tumor suppressors, and oncoproteins are ubiquitinated. However, little is known about the role of ubiquitin signaling in controlling RB-family proteins. A systems genetics analysis of CRISPR/Cas9 screens suggested the potential regulation of the RB-network by cyclin F, a substrate recognition receptor for the SCF family of E3 ligases. We demonstrate that RBL2/p130 is a direct substrate of SCFcyclin F. We map a cyclin F regulatory site to a flexible linker in the p130 pocket domain, and show that this site mediates binding, stability, and ubiquitination. Expression of a mutant version of p130, which cannot be ubiquitinated, severely impaired proliferative capacity and cell cycle progression. Consistently, we observed reduced expression of cell cycle gene transcripts, as well a reduced abundance of cell cycle proteins, analyzed by quantitative, iterative immunofluorescent imaging. These data suggest a key role for SCFcyclin F in the CDK-RB network and raise the possibility that aberrant p130 degradation could dysregulate the cell cycle in human cancers.