2. Academic Validation
  3. USP13 promotes colorectal cancer progression by deubiquitinating and stabilizing HIF-1α

USP13 promotes colorectal cancer progression by deubiquitinating and stabilizing HIF-1α

  • Cell Commun Signal. 2025 Nov 21;23(1):502. doi: 10.1186/s12964-025-02514-3.
Bo Gu # 1,  Si-Yu Chang # 2,  Ke-Ke Li 1,  Bai-Qi Wang 3,  Shao-Bo Ke 4,  Xiao-Dong Zhang 5 6 7,  Run-Lei Du 8 9
Affiliations

Affiliations

  • 1 College of Life Sciences & Renmin Hospital, Wuhan University, Wuhan, Hubei, 430072, China.
  • 2 Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, University of South China, Hengyang, Hunan, 421001, China.
  • 3 Department of Radiation Oncology, For Prevention and Treatment of Breast & Thyroid Disease in Hunan Province, The Second Affiliated Hospital University of South China Clinical Research Cente, Hengyang, Hunan, 421001, China.
  • 4 College of Life Sciences & Renmin Hospital, Wuhan University, Wuhan, Hubei, 430072, China. [email protected].
  • 5 College of Life Sciences & Renmin Hospital, Wuhan University, Wuhan, Hubei, 430072, China. [email protected].
  • 6 Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, University of South China, Hengyang, Hunan, 421001, China. [email protected].
  • 7 Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi of Guangxi Higher Education Institutions, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, China. [email protected].
  • 8 College of Life Sciences & Renmin Hospital, Wuhan University, Wuhan, Hubei, 430072, China. [email protected].
  • 9 Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, University of South China, Hengyang, Hunan, 421001, China. [email protected].
  • # Contributed equally.
PMID: 41272808 DOI: 10.1186/s12964-025-02514-3
Abstract

Background: Hypoxia-inducible factor-1α (HIF-1α) is a key transcriptional regulator in tumor progression, tightly controlled by ubiquitination-mediated proteasomal degradation. While multiple deubiquitinases (DUBs) stabilize HIF-1α, the role of ubiquitin specific peptidase 13 (USP13) in colorectal Cancer (CRC) remained undefined. This study aimed to elucidate whether USP13 regulates HIF-1α stability and contributes to CRC pathogenesis.

Methods: USP13-HIF-1α interaction was assessed via co-immunoprecipitation (co-IP), immunofluorescence, and domain mapping. Ubiquitination assays evaluated USP13-mediated HIF-1α deubiquitination using K-specific ubiquitin mutants. Functional impacts were tested in CRC cell lines using CRISPR/Cas9-mediated USP13 knockout and overexpression. In vitro assays included proliferation (CCK-8), colony formation, migration, invasion, and angiogenesis (HUVECs tube formation). In vivo relevance was validated in xenograft models, USP13-knockout mice, and an AOM/DSS-induced CRC model. Clinical correlation used IHC staining of CRC patient tissues and TCGA data analysis.

Results: USP13 directly bound HIF-1α via its C-terminal UBA domain, cleaving K48-linked polyubiquitin chains to stabilize HIF-1α and enhance its transcriptional activity. USP13 knockout reduced HIF-1α levels, suppressed CRC cell proliferation, migration, invasion, and angiogenesis in vitro, and attenuated tumor growth in xenografts. Conversely, USP13 overexpression exacerbated these effects. Clinically, USP13 and HIF-1α levels correlated positively in CRC tissues and with Ki-67 expression. USP13 deficiency in mice reduced tumor burden in AOM/DSS models, decreased vascular density (CD31+), and downregulated VEGFA/Ki-67. Rescue experiments confirmed HIF-1α dependency for USP13-mediated oncogenic effects.

Conclusions: USP13 promotes CRC progression by deubiquitinating and stabilizing HIF-1α, driving tumor growth, metastasis, and angiogenesis. This identifies USP13 as a pro-tumorigenic factor and potential therapeutic target in CRC.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12964-025-02514-3.

Keywords

Colorectal cancer; Deubiquitination; Hypoxia-inducible factor 1α; USP13.

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