USP13 promotes deubiquitination of ZHX2 and tumorigenesis in kidney cancer

Haibiao Xie, Jin Zhou, Xijuan Liu, Yawei Xu, Austin J. Hepperla, Jeremy M. Simon, Tao Wang, Hongwei Yao, Chengheng Liao, Albert S. Baldwin, Kan Gong, Qing Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by the loss of tumor suppressor Von Hippel Lindau (VHL) function. VHL is the component of an E3 ligase complex that promotes the ubiquitination and degradation of hypoxia inducible factor α (HIF-α) (including HIF1α and HIF2α) and Zinc Fingers And Homeoboxes 2 (ZHX2). Our recent research showed that ZHX2 contributed to ccRCC tumorigenesis in a HIF-independent manner. However, it is still unknown whether ZHX2 could be modified through deubiquitination even in the absence of pVHL. Here, we performed a deubiquitinase (DUB) complementary DNA (cDNA) library binding screen and identified USP13 as a DUB that bound ZHX2 and promoted ZHX2 deubiquitination. As a result, USP13 promoted ZHX2 protein stability in an enzymatically dependent manner, and depletion of USP13 led to ZHX2 down-regulation in ccRCC. Functionally, USP13 depletion led to decreased cell proliferation measured by two-dimensional (2D) colony formation and three-dimensional (3D) anchorage-independent growth. Furthermore, USP13 was essential for ccRCC tumor growth in vivo, and the effect was partially mediated by its regulation on ZHX2. Our findings support that USP13 may be a key effector in ccRCC tumorigenesis.

Original languageEnglish (US)
Pages (from-to)e2119854119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number36
DOIs
StatePublished - Sep 6 2022

Keywords

  • ccRCC
  • deubiquitination
  • USP13
  • ZHX2

ASJC Scopus subject areas

  • General

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