TY - JOUR
T1 - PRDM16 suppresses HIF-targeted gene expression in kidney cancer
AU - Kundu, Anirban
AU - Nam, Hyeyoung
AU - Shelar, Sandeep
AU - Chandrashekar, Darshan S.
AU - Brinkley, Garrett
AU - Karki, Suman
AU - Mitchell, Tanecia
AU - Livi, Carolina B.
AU - Buckhaults, Phillip
AU - Kirkman, Richard
AU - Tang, Yawen
AU - Rowe, Glenn C.
AU - Wei, Shi
AU - Varambally, Sooryanarayana
AU - Sudarshan, Sunil
N1 - Funding Information:
The research reported in this article was supported by National Institutes of Health/NCI grant R01CA200653 and Department of Veterans Affairs grant I01BX002930 (S. Sudarshan) and in part by the University of Alabama at Birmingham O’Neal Comprehensive Cancer Center (P30CA013148).
Publisher Copyright:
© 2020 Kundu et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20191005
DO - 10.1084/jem.20191005
M3 - Article
C2 - 32251515
AN - SCOPUS:85086677610
SN - 0022-1007
VL - 217
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 6
M1 - e20191005
ER -