GCN5 participates in KLF4-VEGFA feedback to promote endometrial angiogenesis

Can Cao; Yuling Zhou; Yu Zhang; Yucong Ma; Shujin Du; Lijie Fan; Ruobing Niu; Yingmei Zhang; Ming He

doi:10.1016/j.isci.2022.104509

GCN5 participates in KLF4-VEGFA feedback to promote endometrial angiogenesis

iScience. 2022 Jun 2;25(7):104509. doi: 10.1016/j.isci.2022.104509. eCollection 2022 Jul 15.

Authors

Can Cao¹, Yuling Zhou¹, Yu Zhang¹, Yucong Ma¹, Shujin Du¹, Lijie Fan¹, Ruobing Niu¹, Yingmei Zhang¹, Ming He¹

Affiliation

¹ Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, 3 Xing Yuan Road, Luquan, Shijiazhuang 050200, China.

Abstract

Endometrial angiogenesis is necessary for good endometrial receptivity. Krüppel-like factor 4 (KLF4) is a transcription factor that is essential for regulating angiogenesis. Here we found that vascular endothelial growth factor A (VEGFA) can form a positive feedback loop with KLF4 to promote the proliferation and migration of human endometrial microvascular endothelial cells (HEMECs) and inhibit cell apoptosis. General control non-derepressible 5 (GCN5) is also time-dependent on VEGFA and participates in the KLF4-VEGFA loop. In addition, we found that GCN5 is a succinyltransferase that modulates the succinylation of histones and nonhistones. GCN5 interacts with KLF4 and is recruited to the KLF4-binding site of the VEGFA promoter to succinylate H3K79, which initiates gene transcription epigenetically. For nonhistones, GCN5 succinylates KLF4 that is activated by ERK signaling in HEMECs treated with VEGFA to increase its transcription activity. These results demonstrate KLF4-VEGFA positive feedback loop is regulated by epigenetics, which contributes to endometrial angiogenesis.

Keywords: Biological sciences; Cell biology; Molecular biology.