USP37 promotes deubiquitination of HIF2α in kidney cancer

Kai Hong, Lianxin Hu, Xijuan Liu, Jeremy M. Simon, Travis S. Ptacek, Xingnan Zheng, Chengheng Liao, Albert S. Baldwin, Qing Zhang

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)13023-13032
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number23
DOIs
StatePublished - Jun 9 2020

Keywords

  • CcRCC
  • Deubiquitination
  • HIF2α
  • USP37

ASJC Scopus subject areas

  • General

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    Hong, K., Hu, L., Liu, X., Simon, J. M., Ptacek, T. S., Zheng, X., Liao, C., Baldwin, A. S., & Zhang, Q. (2020). USP37 promotes deubiquitination of HIF2α in kidney cancer. Proceedings of the National Academy of Sciences of the United States of America, 117(23), 13023-13032. https://doi.org/10.1073/pnas.2002567117