2. Academic Validation
  3. YY1 induced USP13 transcriptional activation drives the malignant progression of hepatocellular carcinoma by deubiquitinating WWP1

YY1 induced USP13 transcriptional activation drives the malignant progression of hepatocellular carcinoma by deubiquitinating WWP1

  • Cell Mol Biol Lett. 2025 May 3;30(1):56. doi: 10.1186/s11658-025-00733-7.
Qingwei Zhu # 1 2,  Zibo Yuan # 1 2,  Qiang Huo # 3,  Qiliang Lu 4 5,  Qingsong Wu 2 6,  Junwei Guo 2 7,  Wen Fu 2 8,  Ying Lu 9,  Lei Zhong 10,  Wenzhong Shang 11,  Di Cui 2 12,  Shuangshuang Li 2,  Xin Liu 13,  Kangsheng Tu 14,  Dongsheng Huang 15,  Qiuran Xu 16,  Xiaoge Hu 17 18
Affiliations

Affiliations

  • 1 The Qingdao Medical College of Qingdao University, Qingdao, 266000, China.
  • 2 Zhejiang Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, China.
  • 3 Department of General Surgery, Zhoushan Dinghai Central Hospital (Dinghai District of Zhejiang Provincial People's Hospital), Zhoushan, 316000, China.
  • 4 General Surgery, Cancer Center, Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, China.
  • 5 The Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China.
  • 6 Department of Hepatobiliary, Shandong Provincial Third Hospital, Shandong University, Jinan, 250031, China.
  • 7 The Second Clinical Medical College of Zhejiang, Chinese Medical University, Hangzhou, 310053, China.
  • 8 Cancer Center, Department of Hematology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, China.
  • 9 Department of Haematology, Affiliated People's Hospital of Ningbo University, Ningbo, 315000, China.
  • 10 Department of Laboratory Medicine, Tongxiang Traditional Chinese Medicine Hospital, Tongxiang, 314500, China.
  • 11 Department of Hematology, The first People's Hospital of Fuyang Hangzhou, Hangzhou, 311400, China.
  • 12 General Surgery, Cancer Center, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, China.
  • 13 Zhejiang Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, China. liuxin@hmc.edu.cn.
  • 14 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
  • 15 Zhejiang Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, China. dshuang@hmc.edu.cn.
  • 16 Zhejiang Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, China. xuqiuran@hmc.edu.cn.
  • 17 Zhejiang Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, China. huxiaoge@hmc.edu.cn.
  • 18 General Surgery, Cancer Center, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, China. huxiaoge@hmc.edu.cn.
  • # Contributed equally.
PMID: 40319251 DOI: 10.1186/s11658-025-00733-7
Abstract

Background: Hepatocellular carcinoma (HCC) is the sixth most prevalent Cancer globally and the third leading cause of cancer-related mortality. Protein ubiquitination and deubiquitination play vital roles in human cancers. Ubiquitin-Specific Protease 13 (USP13) is a deubiquitinating enzyme (DUB) that is involved in many cellular processes. However, the mechanism by which USP13 regulates deubiquitination remains largely unknown.

Methods: Clinical data were analyzed via online databases. USP13 expression in HCC cell lines and tissues was analyzed via western blotting and immunohistochemistry. A lentivirus was used to established stable USP13-knockdown and USP13-overexpression cells. Cell Counting Kit-8, colony formation, wound healing, Transwell, and sphere formation assays were used to detect the malignant behaviors of HCC cells in vitro. A subcutaneous mouse model was used to investigate the function of USP13 in vivo. Co-immunoprecipitation, chromatin immunoprecipitation and dual-luciferase reporter assays were conducted to explore the molecular regulation.

Results: USP13 was upregulated in HCC cell lines and tissues, which predicted a poor prognosis in patients with HCC. Functional experiments in which USP13 was overexpressed or depleted revealed the oncogenic role of USP13 in driving HCC progression both in vitro and in vivo. Mechanistically, WW domain-containing ubiquitin E3 Ligase 1 (WWP1) was identified as a binding protein of USP13. Furthermore, USP13 can interact with WWP1 and then remove the K29- and K48-linked polyubiquitination chains from WWP1 to stabilize the WWP1 protein via the ubiquitin-proteasome pathway. Moreover, Yin Yang 1 (YY1) was explored as a new transcription factor of USP13, and YY1 could also upregulate WWP1 expression through USP13. Moreover, YY1 and WWP1 were shown to participate in the oncogenic role of USP13.

Conclusions: Our findings revealed the functional YY1/USP13/WWP1 signaling axis in HCC, identifying a promising therapeutic target for anti-HCC treatment.

Keywords

Deubiquitination; HCC; USP13; WWP1; YY1.

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