학술논문
ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97
Document Type
article
Author
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
Source
Nature Communications, Vol 15, Iss 1, Pp 1-21 (2024)
Subject
Language
English
ISSN
2041-1723
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.