Nam Hyeyoung, Kundu Anirban, Karki Suman, Kirkman Richard L, Chandrashekar Darshan S, Foote Jeremy B, Zhang Guofang, He Wentao, Varambally Sooryanarayana, Ding Han-Fei, Sudarshan Sunil
Department of Urology, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Urology and the University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
Sci Adv. 2025 Jun 6;11(23):eadt3552. doi: 10.1126/sciadv.adt3552. Epub 2025 Jun 4.
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 messenger RNA transcription via NOTCH signaling activation. Collectively, our findings provide innovative insights into the role of metabolic remodeling in ccRCC tumor progression.
透明细胞肾细胞癌（ccRCC）是最常见的肾癌亚型，表现出显著的代谢重编程。我们之前报道过，II类组蛋白去乙酰化酶HDAC7在ccRCC中表达升高。在此，我们证明HDAC7促进肾细胞癌的侵袭性表型和体内肿瘤进展。HDAC7抑制介导支链氨基酸（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患者生存率降低密切相关。抑制BCAA分解代谢可促进SNAIL1的表达，SNAIL1是包括迁移和侵袭在内的侵袭性表型的核心调节因子。HDAC7介导的BCAA分解代谢程序抑制通过NOTCH信号激活促进信使核糖核酸转录。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性见解。
