期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2119854119
关键词
ZHX2; USP13; deubiquitination; ccRCC
资金
- National Cancer Institute (NCI) [R01CA211732, R01CA256833, R21CA223675]
- Cancer Prevention and Research Institute of Texas (CPRIT) [RR190058]
- Developmental Research Program from Kidney Cancer SPORE at University of Texas Southwestern Medical Center - NCI [P50CA196516]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [U54HD079124]
- National Institute of Neurological Disorders and Stroke [P30NS045892]
- Kidney Cancer Research Alliance (KCCure)
This study reveals that USP13 plays a role in promoting tumorigenesis in ccRCC by deubiquitinating and stabilizing ZHX2. Depletion of USP13 decreases ZHX2 levels and inhibits cell proliferation in ccRCC. These findings suggest that USP13 may be a key factor in ccRCC tumorigenesis.
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 alpha (HIF-alpha) (including HIF1 alpha and HIF2 alpha) 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.
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