HDAC7 promotes renal cancer progression by reprogramming branched-chain amino acid metabolism

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-06-04

Hyeyoung Nam, Anirban Kundu, Suman Karki, Richard L. Kirkman, Darshan S. Chandrashekar, Jeremy B. Foote, Guofang Zhang, Wentao He, Sooryanarayana Varambally, Han-Fei Ding, Sunil Sudarshan

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Abstract

Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, exhibits notable metabolic reprogramming. We previously reported elevated HDAC7, a class II histone deacetylase, in ccRCC. Here, we demonstrate that HDAC7 promotes aggressive phenotypes and in vivo tumor progression in RCC. HDAC7 suppresses the expression of genes mediating branched-chain amino acid (BCAA) catabolism. Notably, lower expression of BCAA catabolism genes is strongly associated with worsened survival in ccRCC. Suppression of BCAA catabolism promotes expression of SNAIL1, a central mediator of aggressive phenotypes including migration and invasion. HDAC7-mediated suppression of the BCAA catabolic program promotes SNAI1 messenger RNA transcription via NOTCH signaling activation. Collectively, our findings provide innovative insights into the role of metabolic remodeling in ccRCC tumor progression.

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HDAC7通过重编程支链氨基酸代谢促进肾癌进展

透明细胞肾细胞癌（ccRCC）是肾癌最常见的亚型，表现出显著的代谢重编程。我们之前报道了ccRCC中HDAC7（一种II类组蛋白去乙酰化酶）升高。在这里，我们证明HDAC7促进了RCC的侵袭性表型和体内肿瘤进展。HDAC7抑制支链氨基酸（BCAA）分解代谢的基因表达。值得注意的是，BCAA分解代谢基因的低表达与ccRCC患者的生存恶化密切相关。抑制BCAA分解代谢可促进SNAIL1的表达，SNAIL1是侵袭性表型（包括迁移和侵袭）的中心介质。hdac7介导的BCAA分解代谢程序抑制通过NOTCH信号激活促进SNAI1信使RNA转录。总的来说，我们的研究结果为代谢重塑在ccRCC肿瘤进展中的作用提供了创新的见解。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.