HDAC10 promotes angiogenesis in endothelial cells through the PTPN22/ERK axis.
HDAC10 promotes angiogenesis in endothelial cells through the PTPN22/ERK axis.
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HDAC10通过PTPN22/ERK轴促进内皮细胞血管生成
DOI：
10.18632/oncotarget.18130
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发表时间：
2017-09-22
期刊：
影响因子：
--
通讯作者：
Kang J
中科院分区：
文献类型：
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作者：
Duan B;Ye D;Zhu S;Jia W;Lu C;Wang G;Guo X;Yu Y;Wu C;Kang J
血管生成在包括肿瘤生长在内的许多生理和病理过程中起着重要作用，但对血管生成的分子调控机制还不完全清楚。本研究旨在探讨组蛋白去乙酰化酶10（HDAC 10）在血管生成调控中的作用及其机制。HDAC 10在人脐静脉内皮细胞（HUVECs）中的过表达促进管形成，而从HUVECs中去除HDAC 10则抑制管形成。从机制上讲，HDAC 10过表达增加了细胞外调节激酶1/2（ERK 1/2）的激活，而HDAC 10的耗竭抑制了ERK 1/2的激活。最后，HDAC 10通过使蛋白酪氨酸磷酸酶非受体22型（PTPN 22）的启动子脱乙酰化并抑制PTPN 22的表达来促进ERK 1/2磷酸化，PTPN 22是ERK磷酸化的负调节剂。总的来说，我们的研究结果确定HDAC 10作为血管生成的关键调节因子，并揭示HDAC 10通过结合和脱乙酰化PTPN 22启动子并随后抑制PTPN 22表达，从而增加ERK 1/2磷酸化在此过程中发挥作用。我们的研究表明，HDAC 10是一个潜在的治疗干预，以抑制血管生成和肿瘤生长的目标。
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.