Pro-Proliferative Function of Mitochondrial Sirtuin Deacetylase SIRT3 in Human Melanoma.
Pro-Proliferative Function of Mitochondrial Sirtuin Deacetylase SIRT3 in Human Melanoma.
复制标题
DOI：
10.1016/j.jid.2015.12.026
复制
发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Ahmad N
中科院分区：
文献类型：
--
作者：
George J;Nihal M;Singh CK;Zhong W;Liu X;Ahmad N
黑色素瘤是最具侵袭性的皮肤癌，如果不及早治疗，往往是致命的。因此，需要新的靶向策略来对抗这种肿瘤。本研究的目的是确定线粒体sirtuin SIRT3在黑色素瘤中的作用和功能意义。我们发现，与正常的原代和永生化的人黑素细胞相比，SIRT3在多个人黑色素瘤细胞的mRNA和蛋白质水平上显著过表达。此外，利用人类组织芯片，我们发现与黑色素细胞痣组织相比，SIRT3在临床黑色素瘤组织中显著上调。此外，短发夹状RNA(ShRNA)介导的sirt3在人黑色素瘤细胞中的敲除导致1)细胞增殖、集落形成和细胞迁移减少，2)诱导衰老，表现为SA-β-Gal活性的增加和SahF的形成以及p16INK4a和p21Waf1的基因和蛋白水平的增加，3)细胞周期的G1期停滞，以及4)细胞周期蛋白(D1，E1)和CDKs(2，4，6)的基因和蛋白水平的降低。相反，强迫外源过表达SIRT3促进了Hs294T黑色素瘤细胞和正常永生化的Mel-ST黑素细胞增殖能力的增加。最后，我们发现SIRT3基因敲除显著抑制了体内异种移植模型的肿瘤形成。据我们所知，这是第一项支持SIRT3在黑色素瘤中促进增殖功能的研究。
Melanoma, the most aggressive forms of skin cancer, is often fatal if not treated early. Therefore, novel target-based strategies are required to combat this neoplasm. The objective of this study was to determine the role and functional significance of the mitochondrial sirtuin SIRT3 in melanoma. We found that compared to normal primary and immortalized human melanocytes, SIRT3 is significantly overexpressed in multiple human melanoma cells at mRNA and protein levels. Further, employing human tissue microarray, we found that SIRT3 is significantly upregulated in clinical melanoma tissues, compared to melanocytic nevi tissues. Furthermore, a short hairpin RNA (shRNA)-mediated knockdown of SIRT3 in human melanoma cells resulted in 1) decrease in cellular proliferation, colony formation and cellular migration, 2) induction of senescence as shown by increase in SA-β-Gal activity and formation of SAHF as well as increase in mRNA and protein levels of p16INK4a and p21Waf1, 3) G1-phase arrest of the cell cycle, and 4) decreases in mRNA and protein levels of Cyclins (D1, E1) and Cdks (2, 4, 6). Conversely, forced exogenous overexpression of SIRT3 promoted increase in proliferative potential of Hs294T melanoma cells and normal immortalized Mel-ST melanocytes. Finally, we found that SIRT3 knockdown significantly inhibited tumorigenesis in a xenograft model in vivo. To our knowledge, this is the first study supporting the pro-proliferative function of SIRT3 in melanoma.