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USP13 Promotes Deubiquitination of ZHX2 and Tumorigenesis in Kidney Cancer

ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is characterized by loss of tumor suppressor Von Hippel Lindau (VHL) function. VHL is the component of E3 ligase complex that promotes the ubiquitination and degradation of hypoxia inducible factor alpha (including HIF1alpha and HIF2alpha) and Zinc Fingers And Homeoboxes 2 (ZHX2). Our recent research showed that ZHX2 contributed to ccRCC tumorigenesis in a HIF independent manner. However, it remains unknown whether ZHX2 can be regulated through deubiquitination. Here we performed a deubiquitinase (DUB) cDNA library binding screen and identified USP13 as a novel 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 downregulation in ccRCC. Functionally, USP13 depletion led to decreased cell proliferation measured by 2-D colony formation and 3-D anchorage independent growth. USP was a critical effector on maintaining kidney tumorigenesis in an orthotopic xenograft model and its depletion led to both decreased primary kidney tumorigenesis and spontaneous lung metastasis. Our results suggest that USP13 is a potential new therapeutic target in ccRCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE186717 | GEO | 2022/07/27

REPOSITORIES: GEO

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VHL Substrate Transcription Factor ZHX2 As An Oncogenic Driver In Clear Cell Renal Cell Carcinoma

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USP13 Promotes Deubiquitination of ZHX2 and Tumorigenesis in Kidney Cancer

Project description:USP13 Promotes Deubiquitination of ZHX2 and Tumorigenesis in Kidney Cancer

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