Author:
Pozner Amir,Verma Shiv Prakash,Li Li,Wang Shuxin,Barrott Jared J.,Nelson Mary L.,Yu Jamie S. E.,Negri Gian Luca,Colborne Shane,Hughes Christopher S.,Zhu Ju-Fen,Lambert Sydney L.,Carroll Lara S.,Smith-Fry Kyllie,Stewart Michael G.,Kannan Sarmishta,Jensen Bodrie,Mortenson Katelyn L.,John Cini,Sikdar Saif,Liu Hongrui,Dang Ngoc Ha,Bourdage Jennifer,Li Jinxiu,Vahrenkamp Jeffery M.,Groundland John S.,Wustrack Rosanna,Senger Donna L.,Zemp Franz J.,Mahoney Douglas J.,Gertz Jason,Zhang Xiaoyang,Lazar Alexander J.,Hirst Martin,Morin Gregg B.,Nielsen Torsten O.,Shen Peter S.,Jones Kevin B.
Abstract
AbstractThe 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 (RCC), frustrating efforts to identify therapeutic targets for these rare cancers. Proteomic analysis showed that VCP/p97, an AAA+ ATPase with known segregase function, was 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-distributed with ASPSCR1-TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrated the oncogenic transcriptional signature of ASPSCR1-TFE3, by facilitating assembly of higher-order chromatin conformation structures as demonstrated by HiChIP. Finally, ASPSCR1-TFE3 and VCP demonstrated co-dependence for cancer cell proliferation and tumorigenesisin vitroand in ASPS and RCC mouse models, underscoring VCP’s potential as a novel therapeutic target.
Publisher
Cold Spring Harbor Laboratory