OGT/HIF-2α axis promotes the progression of clear cell renal cell carcinoma and regulates its sensitivity to ferroptosis
Zhou Yang,
Xiyi Wei,
Chengjian Ji,
Xiaohan Ren,
Wei Su,
Yichun Wang,
Jingwan Zhou,
Zheng Zhao,
Pengcheng Zhou,
Kejie Zhao,
Bing Yao,
Ninghong Song,
Chao Qin
Affiliations
Zhou Yang
The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Xiyi Wei
The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
Chengjian Ji
The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
Xiaohan Ren
The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
Wei Su
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
Yichun Wang
The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
Jingwan Zhou
National Experimental Teaching Center of Basic Medical Science, Nanjing Medical University, Nanjing, China
Zheng Zhao
National Experimental Teaching Center of Basic Medical Science, Nanjing Medical University, Nanjing, China
Pengcheng Zhou
National Experimental Teaching Center of Basic Medical Science, Nanjing Medical University, Nanjing, China
Kejie Zhao
National Experimental Teaching Center of Basic Medical Science, Nanjing Medical University, Nanjing, China
Bing Yao
National Experimental Teaching Center of Basic Medical Science, Nanjing Medical University, Nanjing, China; Department of Medical Genetics, Nanjing Medical University, Nanjing, China; Corresponding author
Ninghong Song
The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Corresponding author
Chao Qin
The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Corresponding author
Summary: 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-2α (HIF-2α) (the main driver of the clear cell phenotype) by repressing ubiquitin‒proteasome system-mediated degradation. Interestingly, the OGT/HIF-2α axis conferred ccRCC a high sensitivity to ferroptosis. In conclusion, OGT promotes the progression of VHL-mutated ccRCC by inhibiting the degradation of HIF-2α, and agents that can modulate the OGT/HIF-2α axis may exert therapeutic effects on mutated VHL ccRCC.
