mTORC2 mediate FLCN-induced HIF2α nuclear import and proliferation of clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC), as the most important type of renal carcinoma, has a high incidence and easy metastasis. Folliculin (FLCN) was identified as a tumor suppressor gene. Its deletions and mutations are associated with a potential risk of kidney cancer. At present, the specific molecular mechanism of FLCN-induced proliferation, invasion and migration in clear cell renal cell carcinoma remains elusive. In this study, we demonstrated that FLCN controled cell proliferation, invasion and migration through PI3K/mTORC2 pathway. FLCN combined with HIF2 in various normal and cancerous renal cells, and mTORC2 mediate FLCN effectively alleviated the deterioration of renal cancer cells by degrading HIF2. Silencing of FLCN showed promotion of HIF2 protein expression, which in turn led to an increase in downstream target genes Cyclin D1 and MMP9. Moreover, when interfering with siFLCN, HIF2 degradation rate was delayed, and the time of entry into the nucleus was advanced. Taken together, our study illustrated that mTORC2 promoted the specific molecular mechanism of HIF2 by down-regulated FLCN, and might be a new therapeutic target against renal cancer progression.