HDAC10 promotes angiogenesis in endothelial cells through the PTPN22/ERK axis.

Baoyu Duan,Chuanyue Wu,Wenwen Jia,Songcheng Zhu,Chenqi Lu,Jiuhong Kang,Yangyang Yu,Dan Ye,Guiying Wang,Xudong Guo

doi:10.18632/oncotarget.18130

Abstract

Angiogenesis is crucially involved in many physiological and pathological processes including tumor growth, but the molecular mechanisms regulating angiogenesis are incompletely understood. In this study, we investigated the functions and mechanism of histone deacetylase 10 (HDAC10), a member of the HDAC II family, in regulation of angiogenesis. HDAC10 overexpression in human umbilical vein endothelial cells (HUVECs) promoted tube formation, whereas depletion of HDAC10 from HUVECs inhibited tube formation in vitro and in vivo. Mechanistically, HDAC10 overexpression increased extracellular-regulated kinase 1/2 (ERK1/2) activation, whereas depletion of HDAC10 inhibited ERK1/2 activation. Finally, HDAC10 promoted ERK1/2 phosphorylation by deacetylating the promoter of protein tyrosine phosphatase, non-receptor type 22 (PTPN22) and inhibiting the expression of PTPN22, which is a negative regulator of ERK phosphorylation. Collectively, our results identify HDAC10 as a key regulator of angiogenesis and reveal that HDAC10 functions in this process by binding and deacetylating the PTPN22 promoter and subsequently inhibiting PTPN22 expression, which in turn increases ERK1/2 phosphorylation. Our studies suggest that HDAC10 is a potential target for therapeutic intervention to inhibit angiogenesis and tumor growth.

Highlights

Angiogenesis is a critical and complex biological event in many physiological and pathological processes, such as tumor growth [1,2,3]
We provide evidence showing that histone deacetylase 10 (HDAC10) is an important positive regulator of angiogenesis and that it functions in this process through regulating the PTPN22-extracellular-regulated kinase 1/2 (ERK1/2) signaling axis
We examined whether treating the cells with SCH772984, a specific ERK1/2 inhibitor [36], could inhibit angiogenesis induced by HDAC10 overexpression

Summary

Introduction

Angiogenesis is a critical and complex biological event in many physiological and pathological processes, such as tumor growth [1,2,3]. This progress relies on the coordinated expression of many genes encoding proteins and angiogenic growth factors that activate endothelial cells and lead to extracellular matrix remodeling, endothelial cell migration and proliferation, capillary tube formation, and subsequent maturation of the new blood vessel [4,5,6,7]. Adrenomedullin promotes angiogenesis in HUVECs, which can be blocked with an ERK1/2 inhibitor [14] These studies indicate that ERK1/2 plays a pivotal role in angiogenesis

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Results

Conclusion