Minichromosome maintenance protein family member 6 mediates hepatocellular carcinoma progression by recruiting UBE3A to induce P53 ubiquitination

Xue Zhang; Saiyan Bian; Yao Ni; Linlin Zhou; Chenyu Yang; Chenfeng Zhang; Xieyin Sun; Nuo Xu; Shiyu Xu; Yilang Wang; Shudong Gu; Wenjie Zheng

doi:10.1016/j.ijbiomac.2023.125854

Minichromosome maintenance protein family member 6 mediates hepatocellular carcinoma progression by recruiting UBE3A to induce P53 ubiquitination

Int J Biol Macromol. 2023 Sep 1:248:125854. doi: 10.1016/j.ijbiomac.2023.125854. Epub 2023 Jul 17.

Authors

Xue Zhang¹, Saiyan Bian², Yao Ni², Linlin Zhou², Chenyu Yang¹, Chenfeng Zhang¹, Xieyin Sun², Nuo Xu², Shiyu Xu², Yilang Wang³, Shudong Gu⁴, Wenjie Zheng⁵

Affiliations

¹ Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China; Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.
² Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.
³ Department of Internal Medicine, The Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong, China. Electronic address: oncowang@ntu.edu.cn.
⁴ Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China. Electronic address: gusdnt@ntu.edu.cn.
⁵ Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China; Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China. Electronic address: wenjiezheng@ntu.edu.cn.

PMID: 37460074
DOI: 10.1016/j.ijbiomac.2023.125854

Abstract

With limited therapeutic options for hepatocellular carcinoma (HCC), it is of great significance to investigate the underlying mechanisms and identifying tumor drivers. MCM6, a member of minichromosome maintenance proteins (MCMs), was significantly elevated in HCC progression and associated with poor prognosis. Knockdown of MCM6 significantly inhibited the proliferation and migration of HCC cells with the increased apoptosis ratio and cell cycle arrest, whereas overexpression of MCM6 induced adverse effects. Mechanistically, MCM6 could decrease the P53 activity by inducing the degradation of P53 protein. In addition, MCM6 enhanced the ubiquitination of P53 by recruiting UBE3A to form a triple complex. Furthermore, overexpression of UBE3A significantly rescued the P53 activation and suppression of malignant behaviors mediated by MCM6 inhibition. In conclusion, MCM6 facilitated aggressive phenotypes of HCC cells by UBE3A/P53 signaling, providing potential biomarkers and targets for HCC.

Keywords: Hepatocellular carcinoma; MCM6; Molecular target.

MeSH terms

Carcinoma, Hepatocellular* / pathology
Cell Line, Tumor
Cell Proliferation
Family
Gene Expression Regulation, Neoplastic
Humans
Liver Neoplasms* / pathology
Minichromosome Maintenance Proteins / genetics
Minichromosome Maintenance Proteins / metabolism
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism
Ubiquitination

Substances

Tumor Suppressor Protein p53
Minichromosome Maintenance Proteins
UBE3A protein, human
Ubiquitin-Protein Ligases