Sirtuin 2 (SIRT2) is one of seven mammalian homologs of silent information regulator 2 (Sir2) and an NAD⁺‐dependent deacetylase; however, its critical role in lymphangiogenesis remains to be explored. We investigate SIRT2 mediated regulation of vascular endothelial growth factor D (VEGFD) expression and lymphangiogenesis by deacetylating endothelial PAS domain protein 1 (EPAS1) in head and neck cancer (HNC) in vitro and in vivo. In this study, we report that SIRT2, rather than other members of the Sir2 family, reduces the expression of VEGFD and lymphangiogenesis in hypoxia‐induced HNC cells and transplanted HNC mice models by reducing EPAS1 acetylation at Lys674 and decreasing the transcriptional activity of EPAS1 target genes. The expression of SIRT2 was closely related to the expression of VEGFD, lymphangiogenesis in subcutaneously transplanted mice models, and lymphangiogenesis in patients with HNC. Our results suggest that SIRT2 plays a central role in tumor lymphangiogenesis via deacetylating EPAS1 protein. Reagents targeting the NAD⁺‐dependent deacetylase activity of SIRT2 would be beneficial for inhibiting tumor lymphangiogenesis and treating other hypoxia‐related diseases.

中文翻译：

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SIRT2通过使人头颈部癌中的EPAS1脱乙酰基来调节VEGFD相关的淋巴管生成。

Sirtuin 2（SIRT2）是沉默信息调节因子2（Sir2）和NAD ⁺的七个哺乳动物同源物之一依赖的脱乙酰酶; 然而，其在淋巴管生成中的关键作用仍有待探索。我们调查SIRT2介导的血管内皮生长因子D（VEGFD）的表达和淋巴管生成的脱乙酰化，在体外和体内在头颈癌（HNC）中的内皮PAS域蛋白1（EPAS1）。在这项研究中，我们报道SIRT2，而不是Sir2家族的其他成员，通过减少Lys674处的EPAS1乙酰化并降低EPAS1靶标的转录活性，降低了低氧诱导的HNC细胞和移植的HNC小鼠模型中VEGFD的表达和淋巴管生成。基因。SIRT2的表达与VEGFD的表达，皮下移植小鼠模型中的淋巴管生成以及HNC患者的淋巴管生成密切相关。我们的结果表明，SIRT2通过使EPAS1蛋白脱乙酰化而在肿瘤淋巴管生成中发挥重要作用。针对NAD的试剂SIRT2的⁺依赖性脱乙酰基酶活性对于抑制肿瘤淋巴管生成和治疗其他与缺氧相关的疾病是有益的。