Ku80 promotes melanoma growth and regulates antitumor effect of melatonin by targeting HIF1-α dependent PDK-1 signaling pathway

• Published in: Redox biology 2019-07, Vol.25, p.101197, Article 101197
• Main Authors: Liu, Tianze, Jin, Lizi, Chen, Miao, Zheng, Zongheng, Lu, Wenjing, Fan, Wenhua, Li, Liren, Zheng, Fufu, Zhu, Qiaohua, Qiu, Huijuan, Liu, Jiani, Chen, Manyu, Tian, Chunfang, Hu, Zheng, Zhang, Changlin, Luo, Meihua, Li, Jian, Kang, Tiebang, Yang, Lukun, Li, Yizhuo, Deng, Wuguo
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Female; HIF1-α; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Ku Autoantigen - metabolism; Ku80; Male; Melanoma; Melanoma - metabolism; Melanoma - pathology; Melatonin; Melatonin - pharmacology; Mice, Nude; Middle Aged; Models, Biological; PDK-1; Prognosis; Promoter Regions, Genetic - genetics; Protein Binding - drug effects; Pyruvate Dehydrogenase Acetyl-Transferring Kinase - genetics; Pyruvate Dehydrogenase Acetyl-Transferring Kinase - metabolism; RNA, Small Interfering - metabolism; Signal Transduction - drug effects; Transcription, Genetic - drug effects
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2019.101197

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-α dependent, and melatonin degraded HIF1-α 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-α dependent PDK-1 signaling pathway, suggesting that Ku80 may be a potential molecular target for melanoma treatment.