Ku80 promotes melanoma growth and regulates antitumor effect of melatonin by targeting HIF1-α dependent PDK-1 signaling pathway
Ku80 promotes melanoma growth and regulates antitumor effect of melatonin by targeting HIF1-α dependent PDK-1 signaling pathway
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Ku80通过靶向HIF1-α依赖的PDK-1信号通路促进黑色素瘤生长并调节褪黑素的抗肿瘤作用
DOI：
10.1016/j.redox.2019.101197
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发表时间：
2019-07-01
期刊：
影响因子：
11.4
通讯作者：
Deng, Wuguo
中科院分区：
文献类型：
--
作者：
Liu, Tianze;Jin, Lizi;Deng, Wuguo
黑色素瘤是最恶性和侵袭性的癌症之一，具有高癌症相关死亡率。然而，目前还不清楚Ku 80是否调节人类黑色素瘤的肿瘤生长。在这项研究中，我们筛选了一个靶向6024个人类基因的siRNA文库，并确定Ku 80作为黑色素瘤细胞中潜在的治疗靶点。Ku 80基因的敲除可显著抑制黑色素瘤细胞的增殖并诱导细胞凋亡，增强褪黑素在体内外的抗黑色素瘤作用。然而，Ku 80的过表达促进了黑色素瘤的生长，并增加了黑色素瘤细胞对褪黑激素的不敏感性。从机制上讲，我们发现Ku 80与PDK 1启动子结合并激活PDK 1的转录。此外，我们发现Ku 80在PDK-1启动子的结合是HIF 1-α依赖性的，并且褪黑激素在黑色素瘤细胞中降解HIF 1-α。此外，临床数据显示，Ku 80和PDK-1蛋白的表达呈正相关，并在黑色素瘤患者的肿瘤组织中升高，Ku 80的高表达预示着黑色素瘤的预后不良。综上所述，Ku 80通过靶向HIF 1-α依赖的PDK-1信号通路促进黑色素瘤生长并调节褪黑素的抗肿瘤活性，提示Ku 80可能是黑色素瘤治疗的潜在分子靶点。
Melanoma is one of the most malignant and aggressive cancers with high cancer-related deaths. However, it is unclear whether Ku80 regulates tumor growth in human melanoma. In this study, we screened a siRNA library targeting 6024 human genes and identified Ku80 as a potential therapeutic target in melanoma cells. Knockdown of Ku80 significantly suppressed melanoma cell proliferation and induced apoptosis, as well as enhanced the antitumor effect of melatonin in melanoma in vitro and in vivo. Overexpression of Ku80, however, promoted melanoma growth and increased the insensitivity of melanoma cells to melatonin. Mechanistically, we found that Ku80 bound to the PDK1 promoter and activated the transcription of PDK1. Moreover, we showed that the binding of Ku80 at the PDK-1 promoter was HIF1-alpha dependent, and melatonin degraded HIF1-alpha in melanoma cells. Furthermore, clinical data revealed that the expression of Ku80 and PDK-1 proteins were positively correlated and elevated in the tumor tissues of melanoma patients, and high expression of Ku80 predicted a poor prognosis in melanoma. Collectively, our study demonstrated that Ku80 promoted melanoma growth and regulated antitumor activity of melatonin by targeting HIF1-alpha dependent PDK-1 signaling pathway, suggesting that Ku80 may be a potential molecular target for melanoma treatment.