SIRT6 histone deacetylase functions as a potential oncogene in human melanoma.
SIRT6 histone deacetylase functions as a potential oncogene in human melanoma.
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DOI：
10.18632/genesandcancer.153
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发表时间：
2017-09
期刊：
影响因子：
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通讯作者：
Ahmad N
中科院分区：
文献类型：
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作者：
Garcia-Peterson LM;Ndiaye MA;Singh CK;Chhabra G;Huang W;Ahmad N
黑色素瘤是一种侵袭性皮肤癌，如果不及早诊断，可能会迅速转移并致命。尽管最近的治疗取得了进展，但黑色素瘤的治疗仍然很困难。因此，需要新的分子靶点和策略来治疗这种肿瘤。本研究旨在确定 Sirtuin SIRT6 在黑色素瘤中的作用。采用一组人类黑色素瘤细胞和正常人类黑色素细胞，我们发现黑色素瘤细胞中 SIRT6 mRNA 和蛋白质显着上调。此外，使用组织微阵列结合定量 Vectra 分析，我们证明了 SIRT6 在人类黑色素瘤组织中显着过度表达。在 A375 和 Hs 294T 人黑色素瘤细胞中，慢病毒短发夹 RNA 介导的 SIRT6 敲低显着降低了细胞生长、活力和集落形成，诱导 G1 期停滞并增加了衰老相关的 β-半乳糖苷酶染色。由于自噬在黑色素瘤中很重要并且与 SIRT6 相关，因此我们使用 qPCR 阵列来研究 A375 细胞中 SIRT6 的敲低。我们发现多个基因和/或蛋白质存在显着调节（AKT1、ATG12、ATG3、ATG7、BAK1、BCL2L1、CLN3、CTSB、CTSS、DRAM2、HSP90AA1、IRGM、NPC1、SQSTM1、TNF 和 BECN1 减少；GAA、ATG10 增加）。我们的数据表明，SIRT6 表达增加可能通过衰老和自噬相关途径促进黑色素瘤的发生和/或进展。
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.