PCDHGC3 silencing promotes renal carcinoma metastasis via mTOR/HIF2a and lipid metabolism rewiring

Clustered 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 of PCDHGC3 is linked to decreased survival in neuroendocrine cancer patients. This study investigates PCDHGC3s role in clear cell renal cell carcinoma (ccRCC). We found that decreased PCDHGC3 expression is associated with lower survival and advanced disease stage in ccRCC patients. shRNA-mediated PCDHGC3 silencing in renal cancer cell lines significantly increased cell proliferation, invasion, and survival. In orthotopic mouse models, PCDHGC3 silencing promoted metastasis. The mTOR and HIF2 pathways were identified as downstream targets activated by PCDHGC3 loss. Inhibition of these pathways counteracted the effects of PCDHGC3 silencing, highlighting their importance in tumor progression. Proteomic and metabolomic analyses showed that PCDHGC3 silencing 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 emphasizes PCDHGC3s impact on ccRCC metastasis and suggests mTOR or HIF2 inhibitors as potential therapies for PCDHGC3-deficient patients.