HDAC10 promotes angiogenesis in endothelial cells through the PTPN22/ERK axis
HDAC10 promotes angiogenesis in endothelial cells through the PTPN22/ERK axis
复制标题
HDAC10通过PTPN22/ERK轴促进内皮细胞血管生成
作者：
段宝玉;康九红;吴传跃;朱颂成;叶丹;贾文文
血管生成参与包括肿瘤生长在内的许多生理和病理过程，但调控血管生成的分子机制尚不完全清楚。在本研究中，我们研究了组蛋白脱乙酰酶10(HDAC10)在血管生成调控中的功能和机制。HDAC10在人脐静脉内皮细胞(HUVECs)中过表达可促进血管形成，而在体内外缺失HDAC10则抑制血管形成。在机制上，高表达HDAC10可促进细胞外调节的激酶1/2(ERK1/2)的激活，而缺失HDAC10则抑制ERK1/2的激活。最后，HDAC10通过去乙酰化非受体22蛋白酪氨酸磷酸酶(PTPN22)启动子和抑制ERK磷酸化负调控因子PTPN22的表达来促进ERK1/2的磷酸化。总之，我们的结果确认HDAC10是血管生成的关键调节因子，并揭示了HDAC10通过结合和去乙酰化PTPN22启动子，随后抑制PTPN22的表达，进而增加ERK1/2的磷酸化而在这一过程中发挥作用。我们的研究表明，HDAC10是抑制血管生成和肿瘤生长的治疗干预的潜在靶点。
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.