Nature Communications (Feb 2024)
ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97
- 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,
- Lara S. Carroll,
- Kyllie Smith-Fry,
- Michael G. Stewart,
- Sarmishta Kannan,
- Bodrie Jensen,
- Cini M. John,
- Saif Sikdar,
- Hongrui Liu,
- Ngoc Ha Dang,
- Jennifer Bourdage,
- Jinxiu Li,
- Jeffery M. Vahrenkamp,
- Katelyn L. Mortenson,
- John S. Groundland,
- Rosanna Wustrack,
- Donna L. Senger,
- Franz J. Zemp,
- Douglas J. Mahoney,
- Jason Gertz,
- Xiaoyang Zhang,
- Alexander J. Lazar,
- Martin Hirst,
- Gregg B. Morin,
- Torsten O. Nielsen,
- Peter S. Shen,
- Kevin B. Jones
Affiliations
- Amir Pozner
- Department of Orthopaedics, University of Utah
- Li Li
- Department of Orthopaedics, University of Utah
- Shiv Prakash Verma
- Department of Orthopaedics, University of Utah
- Shuxin Wang
- Department of Biochemistry, University of Utah
- Jared J. Barrott
- Department of Orthopaedics, University of Utah
- Mary L. Nelson
- Department of Orthopaedics, University of Utah
- Jamie S. E. Yu
- Department of Pathology, 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
- Department of Orthopaedics, University of Utah
- Sydney L. Lambert
- Department of Orthopaedics, University of Utah
- Lara S. Carroll
- Department of Orthopaedics, University of Utah
- Kyllie Smith-Fry
- Department of Orthopaedics, University of Utah
- Michael G. Stewart
- Department of Orthopaedics, University of Utah
- Sarmishta Kannan
- Department of Orthopaedics, University of Utah
- Bodrie Jensen
- Department of Orthopaedics, University of Utah
- Cini M. John
- Department of Microbiology, Immunology and Infectious Disease, University of Calgary
- Saif Sikdar
- Department of Microbiology, Immunology and Infectious Disease, University of Calgary
- Hongrui Liu
- Department of Microbiology, Immunology and Infectious Disease, University of Calgary
- Ngoc Ha Dang
- Department of Oncology, Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Jennifer Bourdage
- Department of Oncology, Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Jinxiu Li
- Department of Orthopaedics, University of Utah
- Jeffery M. Vahrenkamp
- Department of Oncological Sciences, University of Utah
- Katelyn L. Mortenson
- Department of Oncological Sciences, University of Utah
- John S. Groundland
- Department of Orthopaedics, University of Utah
- Rosanna Wustrack
- Department of Orthopaedic Surgery, University of California San Francisco
- Donna L. Senger
- Department of Oncology, Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Franz J. Zemp
- Department of Orthopaedic Surgery, University of California San Francisco
- Douglas J. Mahoney
- Department of Orthopaedic Surgery, University of California San Francisco
- Jason Gertz
- Department of Oncological Sciences, University of Utah
- Xiaoyang Zhang
- Department of Oncological Sciences, University of Utah
- Alexander J. Lazar
- Departments of Anatomic Pathology, Translational Molecular Pathology and Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Martin Hirst
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer
- Gregg B. Morin
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer
- Torsten O. Nielsen
- Department of Pathology, University of British Columbia
- Peter S. Shen
- Department of Biochemistry, University of Utah
- Kevin B. Jones
- Department of Orthopaedics, University of Utah
- DOI
- https://doi.org/10.1038/s41467-024-45280-5
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 21
Abstract
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.
