DNA repair systems are abnormally active in most hepatocellular carcinoma (HCC) cells due to accumulated mutations, resulting in elevated DNA repair capacity and resistance to chemotherapy and radiotherapy. Thus, targeting DNA repair mechanisms is a common treatment approach in HCC to sensitize cancer cells to DNA damage. In this study, we examined the anti-HCC effects of melatonin and elucidated the regulatory mechanisms. The results of functional assays showed that in addition to inhibiting the proliferation, migration, and invasion abilities of HCC cells, melatonin suppressed their DNA repair capacity, thereby promoting the cytotoxicity of chemotherapy and radiotherapy. Whole-transcriptome and gain- and loss-of-function analyses revealed that melatonin induces expression of the long noncoding RNA RAD51-AS1, which binds to RAD51 mRNA to inhibit its translation, effectively decreasing the DNA repair capacity of HCC cells and increasing their sensitivity to chemotherapy and radiotherapy. Animal models further demonstrated that a combination of melatonin and the chemotherapeutic agent etoposide (VP16) can significantly enhance tumor growth inhibition compared with monotherapy. Our results show that melatonin is a potential adjuvant treatment for chemotherapy and radiotherapy in HCC.

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Effective DNA repair enables cancer cells to survive DNA damage induced by chemotherapeutic or radiotherapeutic treatments. Therefore, inhibiting DNA repair pathways is a promising therapeutic strategy for increasing the efficacy of such treatments. In this study, we found that dihydrocoumarin (DHC), a flavoring agent, causes deficiencies in double-stand break (DSB) repair and prolonged DNA damage checkpoint recovery in yeast. Following DNA damage, Rad52 recombinase was revealed to be inhibited by DHC, which results in deficiencies in DSB repair and prolonged DNA damage checkpoint recovery. The deletion of RPD3, a class I histone deacetylase (HDAC), was found to mimic DHC-induced suppression of Rad52 expression, suggesting that the HDAC inhibitor activity of DHC is critical to DSB repair and DNA damage sensitivity. Overall, our findings delineate the regulatory mechanisms of DHC in DSB repair and suggest that it might potentially be used as an inhibitor of the DNA repair pathway in human cells.

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