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 Carroll, Kyllie Smith-Fry, Michael G. Stewart, Sarmishta Kannan, Bodrie Jensen, Cini Mathew John, Saif Sikdar, Hongrui Liu, Ngoc Ha Dang, Jennifer Bourdage, Jinxiu Li, Jeffery M. Vahrenkamp, Katelyn L. Mortenson, John 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 Shen, Kevin B. Jones
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.