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Cell Death & Disease

Cell Death & Disease

IF: 8.1
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USP7 depletion potentiates HIF2α degradation and inhibits clear cell renal cell carcinoma progression

Published:15 October 2024 DOI: 10.1038/s41419-024-07136-0 PMID: 39406703
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

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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Materials
Procduct Name CAS Molecular Formula Supplier Price
MG-132 133407-82-6 C26H41N3O5 427 suppliers $11.00-$9807.90
MG-132 133407-82-6 C26H41N3O5 427 suppliers $11.00-$9807.90
MG-132 133407-82-6 C26H41N3O5 427 suppliers $11.00-$9807.90
MG-132 133407-82-6 C26H41N3O5 427 suppliers $11.00-$9807.90
Afatinib 850140-72-6 C24H25ClFN5O3 367 suppliers $26.00-$1353.25
Afatinib 850140-72-6 C24H25ClFN5O3 367 suppliers $26.00-$1353.25
Afatinib 850140-72-6 C24H25ClFN5O3 367 suppliers $26.00-$1353.25
Afatinib 850140-72-6 C24H25ClFN5O3 367 suppliers $26.00-$1353.25
BIBW2992 850140-72-6 C24H25ClFN5O3 - Inquiry
BIBW2992 850140-72-6 C24H25ClFN5O3 - Inquiry

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