Melatonin antagonizes ovarian aging via YTHDF2-MAPK-NF-κB pathway

Ruigong Zhu; Xian Ji; Xuan Wu; Jiajing Chen; Xuesong Li; Hong Jiang; Haiping Fu; Hui Wang; Zhe Lin; Xin Tang; Shixiu Sun; Qingguo Li; Bingjian Wang; Hongshan Chen

doi:10.1016/j.gendis.2020.08.005

Melatonin antagonizes ovarian aging via YTHDF2-MAPK-NF-κB pathway

Genes Dis. 2020 Aug 21;9(2):494-509. doi: 10.1016/j.gendis.2020.08.005. eCollection 2022 Mar.

Authors

Ruigong Zhu¹, Xian Ji¹, Xuan Wu¹, Jiajing Chen¹, Xuesong Li¹, Hong Jiang¹, Haiping Fu¹, Hui Wang¹, Zhe Lin¹, Xin Tang¹, Shixiu Sun¹, Qingguo Li², Bingjian Wang³, Hongshan Chen^{1

2

4

3}

Affiliations

¹ Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China.
² Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210003, PR China.
³ Department of Cardiology, Huai'an First People's Hospital Affiliated with Nanjing Medical University, Huai'an, Jiangsu 223399, PR China.
⁴ Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, PR China.

Abstract

Cellular senescence is closely associated with age-related diseases. Ovarian aging, a special type of organ senescence, is the pathophysiological foundation of the diseases of the reproductive system. It is characterized by the loss of integrity of the surface epithelium and a gradual decrease in the number of human ovarian surface epithelial cells (HOSEpiCs). To contribute to the research on delaying ovarian aging, we aimed to investigate the novel epigenetic mechanism of melatonin in protecting HOSEpiCs. We discovered that melatonin has antagonistic effects against the oncogene-induced senescence (OIS) of HOSEpiCs. Mechanistically, the oncogene Ras decreased the expression of YTHDF2, which is the reader of RNA-m⁶A, by stimulating the generation of reactive oxygen species (ROS). Moreover, we found that the suppression of YTHDF2 increased the expression of MAP2K4 and MAP4K4 by enhancing the stability of the transcription of their mRNAs, thereby upregulating the expression of the senescence-associated secretory phenotype (SASP) through the activation of the MAP2K4 and MAP4K4-dependent nuclear factor-κB (NF-κB) signaling pathways. We further determined that melatonin has antagonistic effects against the OIS of HOSEpiCs by inhibiting the ROS-YTHDF2-MAPK-NF-κB pathway. These findings provide key insights into the potential avenues for preventing and treating ovarian aging.

Keywords: Gene expression; Inflammation; Melatonin; Senescence; YTHDF2.