2. Academic Validation
  3. USP7 depletion potentiates HIF2α degradation and inhibits clear cell renal cell carcinoma progression

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

  • Cell Death Dis. 2024 Oct 15;15(10):749. doi: 10.1038/s41419-024-07136-0.
Rongfu Tu # 1,  Junpeng Ma # 2 3 4,  Yule Chen # 5,  Ye Kang 6,  Doudou Ren 6,  Zeqiong Cai 6,  Ru Zhang 6,  Yiwen Pan 7,  Yijia Liu 7,  Yanyan Da 2 3 4,  Yao Xu 6,  Yahuan Yu 8,  Donghai Wang 9,  Jingchao Wang 10,  Yang Dong 11,  Xinlan Lu 12,  Chengsheng Zhang 13 14 15 16 17
Affiliations

Affiliations

  • 1 The First Affiliated Hospital of Xi'an Jiaotong University, Center for Precision Cancer Medicine, MED-X Institute, 710000, Xi'an, China. rongfutu@xjtu.edu.cn.
  • 2 The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Center for Molecular Diagnosis and Precision Medicine, 1519 Dongyue Dadao, 330209, Nanchang, China.
  • 3 The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Department of Clinical Laboratory, 1519 Dongyue Dadao, 330209, Nanchang, China.
  • 4 The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, 1519 DongYue Dadao, 330209, Nanchang, China.
  • 5 Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, 710000, Xi'an, China.
  • 6 The First Affiliated Hospital of Xi'an Jiaotong University, Center for Precision Cancer Medicine, MED-X Institute, 710000, Xi'an, China.
  • 7 The First Affiliated Hospital of Xi'an Jiaotong University, Precision Medicine Center, 710000, Xi'an, China.
  • 8 Department of Nephrology, The Affiliated Hospital of Qingdao University, 266100, Qingdao, China.
  • 9 Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, 430071, Wuhan, China.
  • 10 Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, 518055, Shenzhen, China.
  • 11 Department of Pathology, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
  • 12 Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, 710000, Xi'an, China.
  • 13 The First Affiliated Hospital of Xi'an Jiaotong University, Center for Precision Cancer Medicine, MED-X Institute, 710000, Xi'an, China. ndyfy09564@ncu.edu.cn.
  • 14 The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Center for Molecular Diagnosis and Precision Medicine, 1519 Dongyue Dadao, 330209, Nanchang, China. ndyfy09564@ncu.edu.cn.
  • 15 The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Department of Clinical Laboratory, 1519 Dongyue Dadao, 330209, Nanchang, China. ndyfy09564@ncu.edu.cn.
  • 16 The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, 1519 DongYue Dadao, 330209, Nanchang, China. ndyfy09564@ncu.edu.cn.
  • 17 Department of Medical Genetics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 DongYue Dadao, 330209, Nanchang, China. ndyfy09564@ncu.edu.cn.
  • # Contributed equally.
PMID: 39406703 DOI: 10.1038/s41419-024-07136-0
Abstract

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

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