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Androgen receptor and MYC equilibration centralizes on developmental super-enhancer

Author

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  • Haiyang Guo

    (Shandong University
    Shandong Engineering & Technology Research Center for Tumor Marker Detection
    Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory)

  • Yiming Wu

    (Beth Israel Deaconess Medical Center and Harvard Medical School
    Fudan University)

  • Mannan Nouri

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Sandor Spisak

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Joshua W. Russo

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Adam G. Sowalsky

    (National Cancer Institute, National Institutes of Health)

  • Mark M. Pomerantz

    (Harvard Medical School)

  • Zhao Wei

    (Qilu Hospital of Shandong University)

  • Keegan Korthauer

    (University of British Columbia)

  • Ji-Heui Seo

    (Harvard Medical School)

  • Liyang Wang

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Seiji Arai

    (Beth Israel Deaconess Medical Center and Harvard Medical School
    Gunma University Hospital)

  • Matthew L. Freedman

    (Harvard Medical School
    Dana-Farber Cancer Institute
    The Eli and Edythe L. Broad Institute)

  • Housheng Hansen He

    (University of Toronto
    University Health Network)

  • Shaoyong Chen

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Steven P. Balk

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

Abstract

Androgen receptor (AR) in prostate cancer (PCa) can drive transcriptional repression of multiple genes including MYC, and supraphysiological androgen is effective in some patients. Here, we show that this repression is independent of AR chromatin binding and driven by coactivator redistribution, and through chromatin conformation capture methods show disruption of the interaction between the MYC super-enhancer within the PCAT1 gene and the MYC promoter. Conversely, androgen deprivation in vitro and in vivo increases MYC expression. In parallel, global AR activity is suppressed by MYC overexpression, consistent with coactivator redistribution. These suppressive effects of AR and MYC are mitigated at shared AR/MYC binding sites, which also have markedly higher levels of H3K27 acetylation, indicating enrichment for functional enhancers. These findings demonstrate an intricate balance between AR and MYC, and indicate that increased MYC in response to androgen deprivation contributes to castration-resistant PCa, while decreased MYC may contribute to responses to supraphysiological androgen therapy.

Suggested Citation

  • Haiyang Guo & Yiming Wu & Mannan Nouri & Sandor Spisak & Joshua W. Russo & Adam G. Sowalsky & Mark M. Pomerantz & Zhao Wei & Keegan Korthauer & Ji-Heui Seo & Liyang Wang & Seiji Arai & Matthew L. Free, 2021. "Androgen receptor and MYC equilibration centralizes on developmental super-enhancer," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27077-y
    DOI: 10.1038/s41467-021-27077-y
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    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. Zhao Wei & Song Wang & Yaning Xu & Wenzheng Wang & Fraser Soares & Musaddeque Ahmed & Ping Su & Tingting Wang & Elias Orouji & Xin Xu & Yong Zeng & Sujun Chen & Xiaoyu Liu & Tianwei Jia & Zhaojian Liu, 2023. "MYC reshapes CTCF-mediated chromatin architecture in prostate cancer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Ning Qing Liu & Irene Paassen & Lars Custers & Peter Zeller & Hans Teunissen & Dilara Ayyildiz & Jiayou He & Juliane Laura Buhl & Eelco Wieger Hoving & Alexander Oudenaarden & Elzo Wit & Jarno Drost, 2023. "SMARCB1 loss activates patient-specific distal oncogenic enhancers in malignant rhabdoid tumors," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. 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.

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