USP7 depletion potentiates HIF2α degradation and inhibits clear cell renal cell carcinoma progression

• DOI: 10.1038/s41419-024-07136-0
• Publication Date: 2024-10-15T17:01:53Z
• Authors: Rongfu Tu; Junpeng Ma; Yule Chen; Ye Kang; Doudou Ren; Zeqiong Cai; Ru Zhang; Yiwen Pan; Yijia Liu; Yanyan Da; Yao Xu; Yahuan Yu; Donghai Wang; Jingchao Wang; Yang Dong; Xinlan Lu; Chengsheng Zhang
• Keywords: Afatinib; Hypoxia-Inducible Factors; Tumor progression

Clear cell renal carcinoma (ccRCC) is characterized by Von Hippel Lindau (VHL) gene loss of function mutation, which leads to the accumulation hypoxia-inducible factor 2α (HIF2α). HIF2α has been well-established as one major oncogenic drivers ccRCC, however, its therapeutic targeting remains a challenge. Through an analysis proteomic data from ccRCCs and adjacent non-tumor tissues, we herein revealed that Ubiquitin-Specific Peptidase 7 (USP7) was upregulated in tumor depletion inhibitors or shRNAs caused significant suppression progression vitro vivo. Mechanistically, USP7 expression activated transcription factors FUBP1 FUBP3, it promotes mainly deubiquitinating stabilizing HIF2α. Moreover, combination afatinib (an ERBB family inhibitor) coordinately induce death suppression. In mechanism, indirectly inhibits accelerates degradation protein, them more profound abundance. These findings reveal FUBPs-USP7-HIF2α regulatory axis underlies ccRCC provides rationale for via combinational treatment inhibitor afatinib.