Sirt2-SUMOylation is essential for its tumor-suppressor function in neuroblastoma

Abstract

Background SUMOylation is an important post-translational modification and participates in a variety of cellular physiological and pathological processes in eukaryotic cells. Sirt2, as a NAD+-dependent deacetylase, usually exerts tumor-suppressor function. However, its SUMOylation roles in cancer cells have not been illustrated. Methods Ni2+-NTA, GST-pull down and immunoprecipitation in vitro and in vivo were used for the Sirt2-SUMOylation or P38-Acetylation assay. Immunofluorescence and Nuclear/Cytosol Fractionation Kit were performed to identify the localization of Sirt2 with or without SUMOylation. The proliferation, soft-agar colony formation, migration and invasion were performed to detect the phenotypes of neuroblastoma cells in vitro, and the xenograft tumor model was conducted to verify Sirt2-SUMOylation role in tumorigenesis in vivo. R2 online database were used for the clinical analysis, including expression, survival curve and pathology stage. Results SUMOylation can occur in Sirt2 protein at both lysine 183 and lysine 340 sites. SUMOylation of Sirt2 does not affect its localization or stability, but involves in the P38-mTORC2-AKT cellular signal transduction via the direct deacetylation on P38. SUMOylation-deficient Sirt2 losses the capability of suppressing tumor processes and neuroblastoma cell shows a resistance to Sirt2-specific inhibitor AK-7. Conclusion We revealed an important function of SUMOylation on Sirt2, which is closely associated with the cellular signal transduction and is essential for suppressing the tumorigenesis in neuroblastoma.