Aberrant SIRT6 expression contributes to melanoma growth: Role of the autophagy paradox and IGF-AKT signaling
Aberrant SIRT6 expression contributes to melanoma growth: Role of the autophagy paradox and IGF-AKT signaling
复制标题
SIRT6 表达异常导致黑色素瘤生长：自噬悖论和 IGF-AKT 信号传导的作用
DOI：
10.1080/15548627.2017.1384886
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发表时间：
2018-01-01
期刊：
影响因子：
13.3
通讯作者：
Li, Chunying
中科院分区：
文献类型：
--
作者：
Wang, Liwen;Guo, Weinan;Li, Chunying
黑色素瘤是最危及生命的癌症之一。黑色素瘤的发病机制尚未完全阐明。近年来，研究发现失调的巨噬/自噬在不同阶段调节黑色素瘤生长中发挥着关键但不一致的作用，其调节机制尚不清楚。组蛋白去乙酰化酶SIRT6 （sirtuin 6）是一种已知的自噬调节因子，它参与了癌症的发展。因此，我们在本研究中试图确定SIRT6在黑色素瘤生长中的作用，并检测其与自噬的可能联系。我们最初观察到，与黑色素细胞痣相比，SIRT6在原发性黑色素瘤中的表达降低，而在转移性黑色素瘤中的表达升高。值得注意的是，SIRT6的表达与自噬生物标志物MAP1LC3/LC3和SQSTM1/p62的表达显著相关。此外，SIRT6在体外以自噬依赖的方式抑制原发性黑色素瘤的生长，但促进转移性黑色素瘤的发展。此外，SIRT6通过IGF-AKT信号通路调控黑色素瘤生长，AKT的干预可以通过调节自噬来部分逆转SIRT6对黑色素瘤生长的影响。最后，我们在体内确定了SIRT6对黑色素瘤发展的影响。综上所述，我们的研究结果表明SIRT6在黑色素瘤不同阶段的双峰表达通过自噬依赖的方式在调节黑色素瘤生长中起着关键作用，这表明SIRT6有可能成为黑色素瘤的生物标志物和治疗靶点。
ABSTRACT Melanoma is among the most life-threatening cancers. The pathogenesis of melanoma has not been fully elucidated. Recently, dysregulated macroautophagy/autophagy has been found to play a critical but inconsistent role in modulating melanoma growth at different stages, with the regulatory mechanism unclear. The histone deacetylase SIRT6 (sirtuin 6) is a known autophagy regulator, and its involvement in cancer development has been reported. Therefore, we sought to determine the role of SIRT6 in melanoma growth and detect its possible link with autophagy in the current study. We initially observed that the expression of SIRT6 decreased in primary melanoma but increased in metastatic melanoma compared with melanocytic nevus. Notably, the expression of SIRT6 was significantly correlated with the expression of autophagy biomarkers including MAP1LC3/LC3 and SQSTM1/p62. Furthermore, SIRT6 suppressed the growth of primary melanoma but promoted metastatic melanoma development in an autophagy-dependent way in vitro. Moreover, SIRT6 exerted its regulation on melanoma growth via the IGF-AKT signaling pathway, and the intervention of AKT could partly reverse the effects of SIRT6 on melanoma growth by regulating autophagy. At last, we determined the effects of SIRT6 on melanoma development in vivo. Taken together, our findings demonstrate that the bimodal expression of SIRT6 at different melanoma stages plays a critical role in regulating melanoma growth through an autophagy-dependent manner, which indicates the potential of SIRT6 to be a biomarker and a therapeutic target in melanoma.