PRDM16 suppresses HIF-targeted gene expression in kidney cancer

作者：Anirban Kundu, Hyeyoung Nam, Sandeep B. 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 · 发表于：The Journal of Experimental Medicine · 年份：2020 · DOI：10.1084/jem.20191005 · 被引用次数：47 · 研究领域：Cancer, Hypoxia, and Metabolism、RNA modifications and cancer、Epigenetics and DNA Methylation

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.