Department of Otolaryngology-Head and Neck Surgery, Gongli Hospital, Second Military Medical University, Shanghai, China.
Department of Otolaryngology-Head and Neck Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Mol Carcinog. 2020 Nov;59(11):1280-1291. doi: 10.1002/mc.23256. Epub 2020 Sep 23.
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.
Sirtuin 2（SIRT2）是沉默信息调节因子 2（Sir2）的七个哺乳动物同源物之一，也是 NAD 依赖性去乙酰化酶；然而，其在淋巴管生成中的关键作用仍有待探索。我们通过在体外和体内对头颈癌（HNC）中去乙酰化血管内皮生长因子 D（VEGFD）表达和淋巴管生成的内皮 PAS 结构域蛋白 1（EPAS1）来研究 SIRT2 介导的 VEGFD 表达和淋巴管生成的调节作用。在这项研究中，我们报告 SIRT2 而不是 Sir2 家族的其他成员通过减少 Lys674 上的 EPAS1 乙酰化和降低 EPAS1 靶基因的转录活性来减少缺氧诱导的 HNC 细胞和移植的 HNC 小鼠模型中 VEGFD 的表达和淋巴管生成。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 患者中的淋巴管生成密切相关。我们的结果表明，SIRT2 通过去乙酰化 EPAS1 蛋白在肿瘤淋巴管生成中发挥核心作用。针对 SIRT2 的 NAD 依赖性去乙酰化酶活性的试剂将有利于抑制肿瘤淋巴管生成和治疗其他与缺氧相关的疾病。
