Collectively, our study has elucidated that Ku80 interacted with HIF1-α regulated melanoma growth and antitumor effect of melatonin through enhancing the expression of PDK1, suggesting that Ku80 may be a potential target and melatonin combined with Ku80 inhibitor may be a more powerful treatment mode for melanoma treatment. The gene discussed is XRCC5; the disease is melanoma.