OGT/HIF-2α axis promotes the progression of clear cell renal cell carcinoma and regulates its sensitivity to ferroptosis

O-GlcNAc transferase (OGT) acts 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 and this upregulation was associated with a worse survival. Moreover, OGT promoted the proliferation, clone formation, and invasion of VHL-mutated ccRCC cells. Mechanistically, OGT increased the protein level of hypoxia-inducible factor-2 alpha (HIF-2 alpha) (the main driver of the clear cell phenotype) by repressing ubiqui-tin-proteasome system-mediated degradation. Interestingly, the OGT/HIF-2 alpha axis conferred ccRCC a high sensitivity to ferroptosis. In conclusion, OGT promotes the progression of VHL-mutated ccRCC by inhibiting the degradation of HIF-2 alpha, and agents that can modulate the OGT/HIF-2 alpha axis may exert therapeutic effects on mutated VHL ccRCC.

Automated summary

OGT is upregulated in ccRCC and its upregulation is associated with worse survival. OGT promotes the proliferation and invasion of VHL-mutated ccRCC cells by inhibiting the degradation of HIF-2α and confers high sensitivity to ferroptosis.