Melatonin sensitizes hepatocellular carcinoma cells to chemotherapy through long non-coding RNA RAD51-AS1-mediated suppression of DNA repair
Journal
Cancers
Journal Volume
10
Journal Issue
9
Pages
320
Date Issued
2018
Author(s)
Abstract
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. ? 2018 by the authors. Licensee MDPI, Basel, Switzerland.
Subjects
DNA repair; Hepatocellular carcinoma; lncRNA-RAD51-AS1; Melatonin; RAD51
SDGs
Other Subjects
etoposide; long untranslated RNA; melatonin; RAD51 AS1; Rad51 protein; transcriptome; unclassified drug; animal experiment; animal model; animal tissue; antineoplastic activity; Article; cancer chemotherapy; cancer radiotherapy; cell invasion; cell migration; cell proliferation; controlled study; DNA repair; drug cytotoxicity; drug potentiation; drug sensitivity; gain of function mutation; gene expression; hepatocellular carcinoma cell line; human; human cell; human tissue; liver cell carcinoma; loss of function mutation; male; mouse; nonhuman; radiosensitivity; RNA binding; RNA translation
Publisher
MDPI AG
Type
journal article