2. Academic Validation
  3. OTUD5 promotes the growth of hepatocellular carcinoma by deubiquitinating and stabilizing SLC38A1

OTUD5 promotes the growth of hepatocellular carcinoma by deubiquitinating and stabilizing SLC38A1

  • Biol Direct. 2024 Apr 24;19(1):31. doi: 10.1186/s13062-024-00475-0.
Yingnan Yang # 1 2 3,  Siying Jia # 3,  Ning Zhu # 2 3,  Xuelian Xiao 3,  Ying Ma 4,  Kangsheng Tu 3,  Yong Guo 5,  Qiuran Xu 6
Affiliations

Affiliations

  • 1 The Second Clinical Medical College of Zhejiang Chinese Medical University, 310053, Hangzhou, China.
  • 2 Zhejiang Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 310014, Hangzhou, China.
  • 3 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, China.
  • 4 Department of Cardiovascular Medicine, The Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, 710018, Xi'an, China.
  • 5 Department of Gastrointestinal Surgery, Shangluo Central Hospital, 726000, Shangluo, China. [email protected].
  • 6 Zhejiang Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 310014, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 38658981 DOI: 10.1186/s13062-024-00475-0
Abstract

Background: Deubiquitinating enzymes (DUBs) cleave ubiquitin on substrate molecules to maintain protein stability. DUBs reportedly participate in the tumorigenesis and tumour progression of hepatocellular carcinoma (HCC). OTU Deubiquitinase 5 (OTUD5), a DUB family member, has been recognized as a critical regulator in bladder Cancer, breast Cancer and HCC. However, the expression and biological function of OTUD5 in HCC are still controversial.

Results: We determined that the expression of OTUD5 was significantly upregulated in HCC tissues. High levels of OTUD5 were also detected in most HCC cell lines. TCGA data analysis demonstrated that high OTUD5 expression indicated poorer overall survival in HCC patients. OTUD5 silencing prominently suppressed HCC cell proliferation, while its overexpression markedly enhanced the proliferation of HCC cells. Mass spectrometry analysis revealed solute carrier family 38 member 1 (SLC38A1) as a candidate downstream target protein of OTUD5. Coimmunoprecipitation analysis confirmed the interaction between OTUD5 and SLC38A1. OTUD5 knockdown reduced and OTUD5 overexpression increased SLC38A1 protein levels in HCC cells. However, OTUD5 alteration had no effect on SLC38A1 mRNA expression. OTUD5 maintained SLC38A1 stability by preventing its ubiquitin-mediated proteasomal degradation. SLC38A1 silencing prominently attenuated the OTUD5-induced increase in HCC cell proliferation. Finally, OTUD5 knockdown markedly suppressed the growth of HCC cells in vivo.

Conclusions: OTUD5 is an oncogene in HCC. OTUD5 contributes to HCC cell proliferation by deubiquitinating and stabilizing SLC38A1. These results may provide a theoretical basis for the development of new anti-HCC drugs.

Keywords

Deubiquitinating enzymes; Hepatocellular carcinoma; OTUD5, SLC38A1, Tumour growth.

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