2. Academic Validation
  3. Ubiquitin-specific protease 13 promotes colorectal cancer progression by stabilizing mitogen-activated protein kinase kinase 3

Ubiquitin-specific protease 13 promotes colorectal cancer progression by stabilizing mitogen-activated protein kinase kinase 3

  • Mol Biomed. 2025 Nov 27;6(1):122. doi: 10.1186/s43556-025-00375-3.
Si-Yu Chang # 1,  Bo Gu # 2,  Yong Xiong 1,  Meng-Si Zhao 1,  Le Li 1,  Yi Liu 1,  Bai-Qi Wang 1,  Guo-Qing Li 1,  Run-Lei Du 3 4,  Xiao-Dong Zhang 5 6
Affiliations

Affiliations

  • 1 National Health Commission Key Laboratory of Birth Defect Research and Prevention, MOE Key Lab of Rare Pediatric Diseases, Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, The Second Affiliated Hospital, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, China.
  • 2 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, 430072, China.
  • 3 National Health Commission Key Laboratory of Birth Defect Research and Prevention, MOE Key Lab of Rare Pediatric Diseases, Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, The Second Affiliated Hospital, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, China. [email protected].
  • 4 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, 430072, China. [email protected].
  • 5 National Health Commission Key Laboratory of Birth Defect Research and Prevention, MOE Key Lab of Rare Pediatric Diseases, Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, The Second Affiliated Hospital, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, China. [email protected].
  • 6 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, 430072, China. [email protected].
  • # Contributed equally.
PMID: 41307804 DOI: 10.1186/s43556-025-00375-3
Abstract

The deubiquitinase Ubiquitin-Specific Protease 13 (USP13) has been implicated in various cancers, yet its precise molecular function and clinical significance in colorectal Cancer (CRC) remain poorly defined. Here, we identify USP13 as a critical regulator of CRC progression through systematic investigation of its impact on oncogenic signaling pathways. Using luciferase-based pathway screening, we discovered that USP13 activates the mitogen-activated protein kinase (MAPK) signaling cascade. USP13 directly interacts with and stabilizes mitogen-activated protein kinase kinase 3 (MKK3), a key upstream kinase of the p38/MAPK pathway, through removal of K48-linked ubiquitination at the K32 residue. This deubiquitination process requires the UBA domain of USP13 and prevents proteasomal degradation of MKK3, leading to enhanced p38 phosphorylation and activation. Functional validation demonstrated that USP13 and MKK3 significantly promotes CRC cell proliferation, migration, and invasion in vitro. Importantly, in vivo xenograft experiments confirmed that USP13-driven tumor growth depends on MKK3 and can be rescued by constitutive p38 activation. Clinical correlation analysis of CRC patient specimens revealed a strong positive correlation between USP13 and MKK3 expression levels, with elevated USP13 expression associated with advanced disease stage. Our findings not only establish the USP13-MKK3-p38 axis as a crucial molecular pathway in CRC progression but also identify USP13 as a promising therapeutic target.

Keywords

Colorectal cancer; Deubiquitination; MKK3; P38 MAPK signaling; Tumor progression; USP13.

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