USP37 promotes deubiquitination of HIF2α in kidney cancer

Significance HIF2α protein up-regulation, caused by loss of VHL tumor suppressor, is a major oncogenic driver in clear cell renal cell carcinoma (ccRCC). It is well-known that HIF2α is targeted by VHL E3 ligase complex for degradation through the ubiquitin-proteasome system. However, whether HIF2α is regulated by deubiquitinase remains largely unknown. In this study, we identified USP37 as a HIF2α deubiquitinase that can bind with and promote HIF2α protein stability. As a result, loss of USP37 can decrease ccRCC cell proliferation as well as ccRCC tumor growth in an orthotopic xenograft model. Our results suggest that USP37 is a potential therapeutic target in ccRCC. Clear cell renal cell carcinoma (ccRCC) is characterized by loss of tumor suppressor Von Hippel Lindau (VHL) function, which leads to accumulation of hypoxia inducible factor α (including HIF1α and HIF2α). HIF2α was previously reported to be one of the major oncogenic drivers in ccRCC, however, its therapeutic targets remain challenging. Here we performed a deubiquitinase (DUB) complementary DNA (cDNA) library binding screen and discovered that ubiquitin-specific peptidase 37 (USP37) is a DUB that binds HIF2α and promotes HIF2α deubiquitination. As a result, USP37 promotes HIF2α protein stability in an enzymatically dependent manner, and depletion of USP37 leads to HIF2α down-regulation in ccRCC. Functionally, USP37 depletion causes decreased cell proliferation measured by MTS, two-dimensional (2D) colony formation as well as three-dimensional (3D) anchorage- independent growth. USP37 is also essential for maintaining kidney tumorigenesis in an orthotopic xenograft model and its depletion leads to both decreased primary kidney tumorigenesis and spontaneous lung metastasis. Our results suggest that USP37 is a potential therapeutic target in ccRCC.

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