Abstract
Melanoma is an aggressive skin cancer that can rapidly metastasize to become fatal, if not diagnosed early. Despite recent therapeutic advances, management of melanoma remains difficult. Therefore, novel molecular targets and strategies are required to manage this neoplasm. This study was undertaken to determine the role of the sirtuin SIRT6 in melanoma. Employing a panel of human melanoma cells and normal human melanocytes, we found significant SIRT6 mRNA and protein upregulation in melanoma cells. Further, using a tissue microarray coupled with quantitative Vectra analysis, we demonstrated significant SIRT6 overexpression in human melanoma tissues. Lentiviral short hairpin RNA-mediated knockdown of SIRT6 in A375 and Hs 294T human melanoma cells significantly decreased cell growth, viability, and colony formation, induced G1-phase arrest and increased senescence-associated beta-galactosidase staining. As autophagy is important in melanoma and is associated with SIRT6, we used a qPCR array to study SIRT6 knockdown in A375 cells. We found significant modulation in several genes and/or proteins (decreases in AKT1, ATG12, ATG3, ATG7, BAK1, BCL2L1, CLN3, CTSB, CTSS, DRAM2, HSP90AA1, IRGM, NPC1, SQSTM1, TNF, and BECN1; increases in GAA, ATG10). Our data suggests that increased SIRT6 expression may contribute to melanoma development and/or progression, potentially via senescence-and autophagy-related pathways.
Highlights
Melanoma is one of the deadliest forms of skin cancer, and can rapidly metastasize to become lethal if not diagnosed early or left untreated
The objective of this study was to determine the role of the nuclear sirtuin SIRT6 in melanoma
While some studies have suggested a tumor suppressor function of SIRT6 in liver and intestinal cancers [18, 21, 22], others have shown that it has oncogenic properties in prostate cancer and non-melanoma skin cancer [23,24,25]
Summary
Melanoma is one of the deadliest forms of skin cancer, and can rapidly metastasize to become lethal if not diagnosed early or left untreated. Significant adverse events, as well as tumor resistance and recurrence frequently prevent these treatments from being completely successful [36]. Even with these advanced treatments, 9,730 deaths are estimated to occur in 2017 in the US due to this neoplasm [1]. Melanoma provides an ideal neoplasm for new molecularly-targeted drug development, since genetic alterations contribute greatly in the pathogenesis of this disease In this direction, our laboratory has been interested in identifying the role and functional significance of the sirtuin family of proteins in melanoma [7,8,9,10,11,12,13]
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