The OGT/HIF-2a axis promotes the progression of clear cell renal cell carcinoma and its targetable vulnerability to ferroptosis
O-GlcNAc transferase (OGT) has been reported to participate in the development of various cancers, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, we found that OGT was upregulated in ccRCC compared with paired nontumor renal tissues and was associated with worse survival. Moreover, OGT promoted the proliferation, clone formation, and invasive abilities of VHL-mutated ccRCC cells. Mechanistically, OGT promoted the expression of hypoxia-inducible factor-2a (HIF-2a) (the main driver of the clear cell phenotype) by repressing ubiquitin?proteasome system-mediated degradation. Interestingly, the OGT/HIF-2a axis confers ccRCC sensitivity to ferroptosis, rendering it vulnerable. In conclusion, OGT promotes the progression of VHL-mutated ccRCC by inhibiting the degradation of HIF-2a. On the other hand, the OGT/HIF-2a axis renders ccRCC vulnerable to ferroptosis, suggesting that ferroptosis inducers are a promising therapy for patients with upregulated OGT and mutated VHL ccRCC. Overall design: Comparative gene expression profiling analysis of RNA-seq data for OGT overexpressed ccRCC cells.