A positive feedback loop between EZH2 and NOX4 regulates nucleus pulposus cell senescence in age-related intervertebral disc degeneration

Chang Liu; Libangxi Liu; Minghui Yang; Bin Li; Jiarong Yi; Xuezheng Ai; Yang Zhang; Bo Huang; Changqing Li; Chencheng Feng; Yue Zhou

doi:10.1186/s13008-020-0060-x

A positive feedback loop between EZH2 and NOX4 regulates nucleus pulposus cell senescence in age-related intervertebral disc degeneration

Cell Div. 2020 Feb 1:15:2. doi: 10.1186/s13008-020-0060-x. eCollection 2020.

Authors

Chang Liu^#¹, Libangxi Liu¹, Minghui Yang¹, Bin Li¹, Jiarong Yi¹, Xuezheng Ai¹, Yang Zhang¹, Bo Huang¹, Changqing Li¹, Chencheng Feng¹, Yue Zhou¹

Affiliation

¹ Department of Orthopedics, Xinqiao Hospital, Army Medical University, Xinqiao Main Street 183, Shapingba District, Chongqing, People's Republic of China.

^# Contributed equally.

Abstract

Background: The senescence of nucleus pulposus (NP) cells plays a vital role in the pathogenesis of intervertebral disc (IVD) degeneration (IDD). NADPH oxidase 4 (NOX4)-associated oxidative stress has been shown to induce premature NP cell senescence. Enhancer of zeste homolog 2 (EZH2) is a crucial gene regulating cell senescence. The aim of this study was to investigate the roles of EZH2 in NOX4-induced NP cell senescence and a feedback loop between EZH2 and NOX4.

Results: The down-regulation of EZH2 and the up-regulation of NOX4 and p16 were observed in the degenerative discs of aging rats. EZH2 regulated NP cell senescence via the H3K27me3-p16 pathway. Also, EZH2 regulated the expression of NOX4 in NP cells through the histone H3 lysine 27 trimethylation (H3K27me3) in the promoter of NOX4 gene. Furthermore, NOX4 down-regulated EZH2 expression in NP cells via the canonical Wnt/β-catenin pathway.

Conclusions: A positive feedback loop between EZH2 and NOX4 is involved in regulating NP cell senescence, which provides a novel insight into the mechanism of IDD and a potential therapeutic target for IDD.

Keywords: Epigenetic histone modification; Intervertebral disc degeneration; Nucleus pulposus cell senescence; Wnt/β-catenin signaling pathway.