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Updated: Dec 8, 2025
Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
Published on: February 27, 2016
SIRT2 modulates VEGFD-associated lymphangiogenesis by deacetylating EPAS1 in human head and neck cancer
An Hu1, Li-Yun Yang1, Jia Liang1
1Department of Otolaryngology-Head and Neck Surgery, Gongli Hospital, Second Military Medical University, Shanghai, China.
Abstract:
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.
Insights
Sirtuin 2 (SIRT2) reduces head and neck cancer lymphangiogenesis by deacetylating EPAS1, thereby lowering VEGFD expression. Targeting SIRT2
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Sirtuin 2 (SIRT2) is an NAD+-dependent deacetylase with an unexplored role in lymphangiogenesis.
- Head and neck cancer (HNC) exhibits complex regulation of tumor growth and metastasis.
Purpose of the Study:
- To investigate the role of SIRT2 in regulating vascular endothelial growth factor D (VEGFD) expression and lymphangiogenesis in HNC.
- To elucidate the mechanism by which SIRT2 influences EPAS1 acetylation and transcriptional activity.
Main Methods:
- In vitro studies using hypoxia-induced HNC cells.
- In vivo studies using HNC xenograft mouse models.
- Analysis of SIRT2 and VEGFD expression correlation in HNC patient samples.
Main Results:
- SIRT2 reduces VEGFD expression and lymphangiogenesis in HNC cells and mouse models.
- SIRT2 deacetylates EPAS1 at Lys674, decreasing its transcriptional activity.
- SIRT2 expression correlates with VEGFD levels and lymphangiogenesis in HNC patients.
Conclusions:
- SIRT2 plays a critical role in tumor lymphangiogenesis in HNC by deacetylating EPAS1.
- Targeting SIRT2's deacetylase activity may offer a therapeutic strategy for inhibiting tumor lymphangiogenesis and treating hypoxia-related diseases.
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