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ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97

Author

Listed:
  • Amir Pozner

    (University of Utah
    University of Utah
    University of Utah)

  • Li Li

    (University of Utah
    University of Utah
    University of Utah)

  • Shiv Prakash Verma

    (University of Utah
    University of Utah
    University of Utah)

  • Shuxin Wang

    (University of Utah)

  • Jared J. Barrott

    (University of Utah
    University of Utah
    University of Utah)

  • Mary L. Nelson

    (University of Utah
    University of Utah
    University of Utah)

  • Jamie S. E. Yu

    (University of British Columbia)

  • Gian Luca Negri

    (Canada’s Michael Smith Genome Sciences Centre, BC Cancer)

  • Shane Colborne

    (Canada’s Michael Smith Genome Sciences Centre, BC Cancer)

  • Christopher S. Hughes

    (Canada’s Michael Smith Genome Sciences Centre, BC Cancer)

  • Ju-Fen Zhu

    (University of Utah
    University of Utah
    University of Utah)

  • Sydney L. Lambert

    (University of Utah
    University of Utah
    University of Utah)

  • Lara S. Carroll

    (University of Utah
    University of Utah
    University of Utah)

  • Kyllie Smith-Fry

    (University of Utah
    University of Utah
    University of Utah)

  • Michael G. Stewart

    (University of Utah
    University of Utah
    University of Utah
    University of Utah)

  • Sarmishta Kannan

    (University of Utah
    University of Utah
    University of Utah)

  • Bodrie Jensen

    (University of Utah
    University of Utah
    University of Utah)

  • Cini M. John

    (University of Calgary)

  • Saif Sikdar

    (University of Calgary)

  • Hongrui Liu

    (University of Calgary)

  • Ngoc Ha Dang

    (University of Calgary)

  • Jennifer Bourdage

    (University of Calgary)

  • Jinxiu Li

    (University of Utah
    University of Utah
    University of Utah)

  • Jeffery M. Vahrenkamp

    (University of Utah
    University of Utah)

  • Katelyn L. Mortenson

    (University of Utah
    University of Utah)

  • John S. Groundland

    (University of Utah
    University of Utah)

  • Rosanna Wustrack

    (University of California San Francisco)

  • Donna L. Senger

    (University of Calgary
    McGill University and Lady Davis Institute for Medical Research)

  • Franz J. Zemp

    (University of California San Francisco)

  • Douglas J. Mahoney

    (University of California San Francisco)

  • Jason Gertz

    (University of Utah
    University of Utah)

  • Xiaoyang Zhang

    (University of Utah
    University of Utah)

  • Alexander J. Lazar

    (The University of Texas MD Anderson Cancer Center)

  • Martin Hirst

    (Canada’s Michael Smith Genome Sciences Centre, BC Cancer
    University of British Columbia)

  • Gregg B. Morin

    (Canada’s Michael Smith Genome Sciences Centre, BC Cancer
    University of British Columbia)

  • Torsten O. Nielsen

    (University of British Columbia)

  • Peter S. Shen

    (University of Utah)

  • Kevin B. Jones

    (University of Utah
    University of Utah
    University of Utah)

Abstract

The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP’s potential as a novel therapeutic target.

Suggested Citation

  • Amir Pozner & Li Li & Shiv Prakash Verma & Shuxin Wang & Jared J. Barrott & Mary L. Nelson & Jamie S. E. Yu & Gian Luca Negri & Shane Colborne & Christopher S. Hughes & Ju-Fen Zhu & Sydney L. Lambert , 2024. "ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45280-5
    DOI: 10.1038/s41467-024-45280-5
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