Open AccessPRDM16 suppresses HIF-targeted gene expression in kidney cancer
Author(s) -
A. Kundu,
Hyeyoung Nam,
Sandeep Shelar,
Darshan S. Chandrashekar,
Garrett J. Brinkley,
Suman Karki,
Tanecia Mitchell,
Carolina B. Livi,
Phillip Buckhaults,
Richard Kirkman,
Yawen Tang,
Glenn C. Rowe,
Shi Wei,
Sooryanarayana Varambally,
Sunil Sudarshan
Publication year - 2020
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20191005
Subject(s) - biology , prdm16 , gene silencing , cancer research , carcinogenesis , epigenetics , gene expression , transcriptome , transcription factor , microbiology and biotechnology , cancer , gene , genetics
Analysis of transcriptomic data demonstrates extensive epigenetic gene silencing of the transcription factor PRDM16 in renal cancer. We show that restoration of PRDM16 in RCC cells suppresses in vivo tumor growth. RNaseq analysis reveals that PRDM16 imparts a predominantly repressive effect on the RCC transcriptome including suppression of the gene encoding semaphorin 5B (SEMA5B). SEMA5B is a HIF target gene highly expressed in RCC that promotes in vivo tumor growth. Functional studies demonstrate that PRDM16’s repressive properties, mediated by physical interaction with the transcriptional corepressors C-terminal binding proteins (CtBP1/2), are required for suppression of both SEMA5B expression and in vivo tumor growth. Finally, we show that reconstitution of RCC cells with a PRDM16 mutant unable to bind CtBPs nullifies PRDM16’s effects on both SEMA5B repression and tumor growth suppression. Collectively, our data uncover a novel epigenetic basis by which HIF target gene expression is amplified in kidney cancer and a new mechanism by which PRDM16 exerts its tumor suppressive effects.