PCDHGC3silencing promotes clear cell renal cell carcinoma metastasis via mTOR/HIF2α and lipid metabolism reprogramming

Abstract

AbstractClustered protocadherins (cPCDH) are widely expressed in the nervous system with known functions, but their roles in cancer, particularly metastasis, are largely unexplored. Our previous research revealed that epigenetic silencing ofPCDHGC3is linked to decreased survival in neuroendocrine cancer patients. This study investigatesPCDHGC3’s role in clear cell renal cell carcinoma (ccRCC). We found that decreasedPCDHGC3expression is associated with lower survival and advanced disease stage in ccRCC patients. shRNA-mediatedPCDHGC3silencing in renal cancer cell lines significantly increased cell proliferation, invasion, and survival. In orthotopic mouse models,PCDHGC3silencing promoted metastasis. The mTOR and HIF2α pathways were identified as downstream targets activated byPCDHGC3loss. Inhibition of these pathways counteracted the effects ofPCDHGC3silencing, highlighting their importance in tumor progression. Proteomic and metabolomic analyses showed thatPCDHGC3silencing led to overexpression of proteins involved in fatty acid and cholesterol synthesis, increasing lipid droplets and shifting lipid metabolism. This metabolic reprogramming characterizes aggressive ccRCC. Our study emphasizesPCDHGC3’s impact on ccRCC metastasis and suggests mTOR or HIF2α inhibitors as potential therapies forPCDHGC3-deficient patients.