Abstract
Osteosarcomas (OS) are highly metastatic and usually lead to poor outcomes. Epithelial-mesenchymal transition (EMT) is reported to be a critical event in metastasis. SIRT2 exerts dual functions in many different tumors. However, the underlying molecular mechanisms of SIRT2 in osteosarcoma cell metastasis and the question of whether SIRT2 regulates EMT have not been fully explored. In this study, we confirmed that SIRT2 was highly-expressed in human osteosarcoma MG63 and Saos-2 cell lines. The viability, migration and invasion of osteosarcoma cells were inhibited by knockdown of SIRT2 and were enhanced by overexpression of SIRT2. Moreover, SIRT2 positively regulated EMT and upregulated the protein levels of the mesenchymal markers N-cadherin and Vimentin and the levels of MMP2 and MMP9. A xenograft mouse model showed that SIRT2 knockdown in osteosarcoma cells led to reduced tumor growth, decreased expression of mesenchymal markers and impaired lung and liver metastasis in vivo. Furthermore, we showed that SIRT2 interacted with and upregulated the protein level of the EMT-associated transcription factor Snail. SIRT2 inhibited Snail degradation via its deacetylase activity. Knockdown of Snail abrogated the promoting effects of SIRT2 on migration and invasion of osteosarcoma cells. In conclusion, SIRT2 plays a crucial role in osteosarcoma metastasis by inhibiting Snail degradation and may serve as a novel therapeutic target to manage osteosarcoma.