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

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 bilat...

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Published in:	Cell reports (Cambridge) Vol. 18; no. 12; pp. 2893 - 2906
Main Authors:	Nargund, Amrita M., Pham, Can G., Dong, Yiyu, Wang, Patricia I., Osmangeyoglu, Hatice U., Xie, Yuchen, Aras, Omer, Han, Song, Oyama, Toshinao, Takeda, Shugaku, Ray, Chelsea E., Dong, Zhenghong, Berge, Mathieu, Hakimi, A. Ari, Monette, Sebastien, Lekaye, Carl L., Koutcher, Jason A., Leslie, Christina S., Creighton, Chad J., Weinhold, Nils, Lee, William, Tickoo, Satish K., Wang, Zhong, Cheng, Emily H., Hsieh, James J.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 21-03-2017 Elsevier
Subjects:	Animals Carcinoma, Renal Cell - genetics Carcinoma, Renal Cell - metabolism Carcinoma, Renal Cell - pathology ccRCC Down-Regulation - genetics epigenetics Gene Deletion Gene Expression Profiling Gene Expression Regulation, Neoplastic genetics HIF1 HMGB Proteins - deficiency HMGB Proteins - metabolism Humans Hydronephrosis - genetics Hydronephrosis - pathology Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Integrases - metabolism Kidney - metabolism Kidney - pathology kidney cancer Kidney Neoplasms - genetics Kidney Neoplasms - metabolism Kidney Neoplasms - pathology Mechanistic Target of Rapamycin Complex 1 - metabolism Mice mouse tumor model MTOR Nuclear Proteins - metabolism Oxidative Phosphorylation PBRM1 Signal Transduction STAT3 STAT3 Transcription Factor - metabolism Transcription Factors - metabolism Transcription, Genetic VHL Von Hippel-Lindau Tumor Suppressor Protein - metabolism kidney cancer PBRM1 ccRCC mouse tumor model genetics STAT3 VHL HIF1 MTOR epigenetics
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Summary:	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. [Display omitted] •PBRM1 is a bona fide tumor suppressor in the pathogenesis of ccRCC•PBRM1 prevents self-perpetuating amplification of HIF1/STAT3 signaling in Vhl−/− cell•Loss of Vhl and Pbrm1 in mouse kidney results in multifocal, transplantable ccRCC•In ccRCC, mTORC1 activation is the third driver event after loss of VHL and PBRM1 Nargund et al. present a three-step process in the pathogenesis of mouse and human clear cell kidney cancer. After the loss of VHL, the loss of SWI/SNF tumor suppressor protein PBRM1/BAF180 further activates HIF1/STAT3 signaling in mouse kidney and positions mTORC1 activation as the preferred third driver event.
Bibliography:	Lead Contact Amrita M. Nargund, Can G. Pham, and Yiyu Dong contributed equally to this work.
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2017.02.074