2. Academic Validation
  3. Oxidative Stress Promotes Liver Cancer Metastasis via RNF25-Mediated E-Cadherin Protein Degradation

Oxidative Stress Promotes Liver Cancer Metastasis via RNF25-Mediated E-Cadherin Protein Degradation

  • Adv Sci (Weinh). 2024 Jan 29:e2306929. doi: 10.1002/advs.202306929.
Zhao Huang 1,  Li Zhou 2,  Jiufei Duan 1,  Siyuan Qin 1,  Jingwen Jiang 3,  Haining Chen 4,  Kui Wang 5,  Rui Liu 6,  Minlan Yuan 7,  Xiangdong Tang 8,  Edouard C Nice 9,  Yuquan Wei 1,  Wei Zhang 10 11,  Canhua Huang 1 10
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China.
  • 3 West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, 610041, China.
  • 4 Colorectal Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 5 West China School of Basic Medical Sciences & Forensic Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 6 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
  • 7 Mental Health Center and Psychiatric Laboratory, The State Key Laboratory of Biotherapy, West China Biomedical Big Data Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
  • 8 Sleep Medicine Center, Department of Respiratory and Critical Care Medicine, Mental Health Center, Translational Neuroscience Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 9 Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3167, Australia.
  • 10 Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, China.
  • 11 Medical Big Data Center, Sichuan University, Chengdu, 610041, China.
PMID: 38286671 DOI: 10.1002/advs.202306929
Abstract

Loss of E-cadherin (ECAD) is required in tumor metastasis. Protein degradation of ECAD in response to oxidative stress is found in metastasis of hepatocellular carcinoma (HCC) and is independent of transcriptional repression as usually known. Mechanistically, protein kinase A (PKA) senses oxidative stress by redox modification in its β catalytic subunit (PRKACB) at Cys200 and Cys344. The activation of PKA kinase activity subsequently induces RNF25 phosphorylation at Ser450 to initiate RNF25-catalyzed degradation of ECAD. Functionally, RNF25 repression induces ECAD protein expression and inhibits HCC metastasis in vitro and in vivo. Altogether, these results indicate that RNF25 is a critical regulator of ECAD protein turnover, and PKA is a necessary redox sensor to enable this process. This study provides some mechanistic insight into how oxidative stress-induced ECAD degradation promotes tumor metastasis of HCC.

Keywords

cancer metastasis; oxidative stress; post-translational modifications; redox signaling.

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