Int J Biol Sci 2022; 18(10):4071-4087. doi:10.7150/ijbs.69495 This issue

Research Paper

A positive feedback loop of CENPU/E2F6/E2F1 facilitates proliferation and metastasis via ubiquitination of E2F6 in hepatocellular carcinoma

Yingyi Liu1,2#, Ye Yao1,2#, Bo Liao1,2#, Hao Zhang1,2, Zhangshuo Yang1,2, Peng Xia1,2, Xiang Jiang1,2, Weijie Ma1,2, Xiaoling Wu1,2, Chengjie Mei1,2, Ganggang Wang1,2, Meng Gao1,2, Kequan Xu1,2, Xiangdong GongYe1,2, Zhixiang Cheng1,2, Ping Jiang1,2, Xi Chen1,2✉, Yufeng Yuan1,2✉

1. Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, PR China.
2. Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430071, Hubei, PR China.
#These authors contributed equally to this study.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Liu Y, Yao Y, Liao B, Zhang H, Yang Z, Xia P, Jiang X, Ma W, Wu X, Mei C, Wang G, Gao M, Xu K, GongYe X, Cheng Z, Jiang P, Chen X, Yuan Y. A positive feedback loop of CENPU/E2F6/E2F1 facilitates proliferation and metastasis via ubiquitination of E2F6 in hepatocellular carcinoma. Int J Biol Sci 2022; 18(10):4071-4087. doi:10.7150/ijbs.69495. Available from https://www.ijbs.com/v18p4071.htm

File import instruction

Abstract

Graphic abstract

Centromere protein U (CENPU), a centromere-binding protein required for cellular mitosis, has been reported to be closely associated with carcinogenesis in multiple malignancies; however, the role of CENPU in hepatocellular carcinoma (HCC) is still unclear. Herein, we investigated its biological role and molecular mechanism in the development of HCC. High CENPU expression in HCC tissue was observed and correlated positively with a poor prognosis in HCC patients. CENPU knockdown inhibited the proliferation, metastasis, and G1/S transition of HCC cells in vivo and in vitro, while ectopic expression of CENPU exerted the opposite effects. Mechanistically, CENPU physically interacted with E2F6 and promoted its ubiquitin-mediated degradation, thus affecting the transcription level of E2F1 and further accelerating the G1/S transition to promote HCC cell proliferation. E2F1 directly binds to the CENPU promoter and increases the transcription of CENPU, thereby forming a positive regulatory loop. Collectively, our findings indicate a crucial role for CENPU in E2F1-mediated signalling for cell cycle progression and reveal a role for CENPU as a predictive biomarker and therapeutic target for HCC patients.

Keywords: Hepatocellular carcinoma, CENPU, E2F6, E2F1, G1/S transition