SIRT6 promotes a mesenchymal, invasive phenotype in melanoma.

Melanoma is a highly aggressive cutaneous malignancy with significant metastatic potential, posing ongoing challenges in elucidating the molecular mechanisms driving its progression. Epithelial-mesenchymal transition (EMT) is a key process that enhances cancer cell migration and invasion, facilitating metastatic dissemination. Sirtuin 6 (SIRT6), a NAD+-dependent enzyme, has been reported to either promote or suppress EMT in a context-dependent manner; however, its function in melanoma remains poorly defined. We previously showed that SIRT6 is overexpressed in melanoma tissues and cells, where it contributes to tumor growth via an autophagy-dependent mechanism. In this study, we further investigated the role of SIRT6 in EMT using melanoma cells with stable overexpression or shRNA-mediated knockdown. Overexpression of SIRT6 enhanced cell proliferation and clonogenic survival and was associated with increased expression of mesenchymal markers and EMT-associated transcription factors. Conversely, SIRT6 knockdown significantly reduced the expression of these genes. Functionally, SIRT6 depletion markedly impaired cell migration and invasion, as demonstrated by wound-healing and Matrigel invasion assays. Collectively, these findings identify SIRT6 as a promoter of an invasive, mesenchymal phenotype in melanoma. Our results support a potential oncogenic role for SIRT6 and highlight its inhibition as a promising therapeutic strategy to limit melanoma progression and metastasis.