SIRT2 modulates VEGFD-associated lymphangiogenesis by deacetylating EPAS1 in human head and neck cancer

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.