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
Date Published2017 Mar 21
KeywordsAnimals, Carcinoma, Renal Cell, DNA-Binding Proteins, Down-Regulation, Gene Deletion, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, HMGB Proteins, Humans, Hydronephrosis, Hypoxia-Inducible Factor 1, alpha Subunit, Integrases, Kidney, Kidney Neoplasms, Mechanistic Target of Rapamycin Complex 1, Mice, Nuclear Proteins, Oxidative Phosphorylation, Signal Transduction, STAT3 Transcription Factor, Transcription Factors, Transcription, Genetic, Von Hippel-Lindau Tumor Suppressor Protein

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.

Alternate JournalCell Rep
PubMed ID28329682
PubMed Central IDPMC5431084
Grant ListK99 CA207871 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA138505 / CA / NCI NIH HHS / United States
R01 HL109054 / HL / NHLBI NIH HHS / United States

Similar Publications