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 and Kevin B. Jones ()
Additional contact information
Amir Pozner: University of Utah
Li Li: University of Utah
Shiv Prakash Verma: University of Utah
Shuxin Wang: University of Utah
Jared J. Barrott: University of Utah
Mary L. Nelson: 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
Sydney L. Lambert: University of Utah
Lara S. Carroll: University of Utah
Kyllie Smith-Fry: University of Utah
Michael G. Stewart: University of Utah
Sarmishta Kannan: University of Utah
Bodrie Jensen: 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
Jeffery M. Vahrenkamp: University of Utah
Katelyn L. Mortenson: University of Utah
John S. Groundland: University of Utah
Rosanna Wustrack: University of California San Francisco
Donna L. Senger: University of Calgary
Franz J. Zemp: University of California San Francisco
Douglas J. Mahoney: University of California San Francisco
Jason Gertz: University of Utah
Xiaoyang Zhang: 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
Gregg B. Morin: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Torsten O. Nielsen: University of British Columbia
Peter S. Shen: University of Utah
Kevin B. Jones: University of Utah

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
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DOI: 10.1038/s41467-024-45280-5

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