HDAC7 promotes renal cancer metastasis by reprogramming branched-chain amino acid metabolism
Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, exhibits significant 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 mRNA transcription via NOTCH signaling activation. Collectively, our findings provide new insights into the role of metabolic remodeling in ccRCC tumor progression. Overall design: RCC cell lines were obtained from ATCC. 769-P cells were cultured in RPMI 1640 medium (Corning Life Science) supplemented with 10% FBS (R&D systems) with 100 U/mL penicillin-streptomycin. CAKI-1 cells were maintained in MEM medium supplemented with 10% FBS and antibiotics. RCC cells (769-P and CAKI-1) were treated without or with BCAA (0.38 mM isoleucine, 0.38 mM leucine, and 0.17 mM valine) for 16 hours. Total RNA from these cultured cells was extracted using the RNeasy Mini Kit (Qiagen).