The histone lysine methyltransferase SETD8 regulates angiogenesis through HES-1 in human umbilical vein endothelial cells

Sang-Hyun Min,Young Kyu Kim,Heejin Lee,Sang A Kim,Seul Lee,Wanil Kim,Ji Hoon Yu,Soo Jin Kim,Sang Wook Park,Junyeop Lee,Dong Kyu Choi

doi:10.1038/s41598-020-69103-x

Abstract

Histone modifications, including histone lysine methylation, regulate gene expression in the vasculature, and targeting tumor blood vessels through histone modification decreases tumor growth. SETD8, a methyltransferase that catalyzes the mono-methylation of histone H4 lysine 20 is known to promote tumorigenesis in various cancers and its high levels of expression are related to poor prognosis. However, the detailed mechanisms by which SETD8 stimulates tumor progression and angiogenesis are still not well understood. Recent studies have demonstrated that, in vitro, BVT-948 efficiently and selectively suppresses SETD8 activity and histone methylation levels. In this study, we showed that BVT-948-mediated SETD8 inhibition in HUVECs results in an inhibition of angiogenesis. Inhibition of SETD8 not only inhibited angiogenesis but also disrupted actin stress fiber formation and induced cell cycle arrest at S phase. These effects were accompanied by increased HES-1 expression levels, decreased osteopontin levels, and a decreased differentiation of human induced pluripotent stem cells into endothelial cells. Interestingly, BVT-948 treatment reduced pathological angiogenesis in mouse OIR model. These data illustrate the mechanisms by which SETD8 regulates angiogenesis and may enable the use of a SETD8 inhibitor to treat various pathological conditions that are known to be associated with excessive angiogenesis, including and tumor growth.

Highlights

Histone modifications, including histone lysine methylation, regulate gene expression in the vasculature, and targeting tumor blood vessels through histone modification decreases tumor growth
It has been reported that diverse histone methyltransferases (HMTs) promote proliferation, invasion, and sprouting during angiogenesis
Because mixed lineage leukemia (MLL) family proteins possess the set catalytic domain in their carboxyl terminus and are known to play a role in angiogenesis[14], we used the MLL1 specific inhibitors MM-102 and WDR-5 to rule out the possibility that the BVT-948 mediated inhibition of human umbilical vein endothelial cells (HUVECs) migration was a result of MLL inhibition

Summary

Introduction

Histone modifications, including histone lysine methylation, regulate gene expression in the vasculature, and targeting tumor blood vessels through histone modification decreases tumor growth. Inhibition of SETD8 inhibited angiogenesis and disrupted actin stress fiber formation and induced cell cycle arrest at S phase These effects were accompanied by increased HES-1 expression levels, decreased osteopontin levels, and a decreased differentiation of human induced pluripotent stem cells into endothelial cells. Several studies have shown that targeting the epigenetic machinery of a tumor’s blood vessels decreases tumor g rowth[4]. Methyltransferases/histone demethylases (HMTs/HDMTs) have been shown to regulate tumor angiogenesis[5] Aberrations in their expression in pathological angiogenesis have highlighted them as potential targets for the development of therapeutics

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Conclusion