The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma.

TitleThe SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma.
Publication TypeJournal Article
Year of Publication2017
AuthorsNargund, AM, Pham, CG, Dong, Y, Wang, PI, Osmangeyoglu, HU, Xie, Y, Aras, O, Han, S, Oyama, T, Takeda, S, Ray, CE, Dong, Z, Berge, M, A Hakimi, A, Monette, S, Lekaye, CL, Koutcher, JA, Leslie, CS, Creighton, CJ, Weinhold, N, Lee, W, Tickoo, SK, Wang, Z, Cheng, EH, Hsieh, JJ
JournalCell Rep
Volume18
Issue12
Pagination2893-2906
Date Published2017 Mar 21
ISSN2211-1247
Abstract

PBRM1 is the second most commonly mutated gene after VHL in clear cell renal cell carcinoma (ccRCC). However, the biological consequences of PBRM1 mutations for kidney tumorigenesis are unknown. Here, we find that kidney-specific deletion of Vhl and Pbrm1, but not either gene alone, results in bilateral, multifocal, transplantable clear cell kidney cancers. PBRM1 loss amplified the transcriptional outputs of HIF1 and STAT3 incurred by Vhl deficiency. Analysis of mouse and human ccRCC revealed convergence on mTOR activation, representing the third driver event after genetic inactivation of VHL and PBRM1. Our study reports a physiological preclinical ccRCC mouse model that recapitulates somatic mutations in human ccRCC and provides mechanistic and therapeutic insights into PBRM1 mutated subtypes of human ccRCC.

DOI10.1016/j.celrep.2017.02.074
Alternate JournalCell Rep
PubMed ID28329682