Abstract
Melatonin exerts antimetastatic effects on liver and breast cancer and also inhibits matrix metalloproteinase (MMP) activity. However, the detailed impacts and underlying mechanisms of melatonin on oral cancer cell metastasis are still unclear. This study showed that melatonin attenuated the 12-O-tetradecanoylphorbol-13-acetate-induced migration of oral cancer cell lines, HSC-3 and OECM-1. Zymography, quantitative real-time PCR, and Western blotting analyses revealed that melatonin lessened MMP-9 enzyme activity as well as the expression of MMP-9 mRNA and protein. Furthermore, melatonin suppressed the phosphorylation of the ERK1/2 signalling pathway, which dampened MMP-9 gene transcription by affecting the expression of transcriptional coactivators, such as CREB-binding protein (CREBBP) and E1A binding protein p300 (EP300), and decreasing histone acetylation in HSC-3 and OECM-1 cells. Examinations on clinical samples exhibited that MMP-9, CREBBP, and EP300 were significantly increased in oral cancer tissues. Moreover, the relative level of CREBBP was positively correlated with the expression of MMP-9 and EP300. In conclusion, we demonstrated that melatonin inhibits the motility of HSC-3 and OECM-1 cells in vitro through a molecular mechanism that involves attenuation of MMP-9 expression and activity mediated by decreased histone acetylation.
Highlights
Head and neck cancer is a common human cancer, and approximately 50% of cases occur in the oral cavity; more than 90% of these cases involve oral squamous cell carcinoma (OSCC) [1]
We demonstrated that melatonin inhibits migration of HSC-3 and OECM-1 oral cancer www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget cells, inhibits the gene expression and enzyme activity of matrix metalloproteinase (MMP)-9, inhibits phosphorylation of ERK1/2, inhibits the expression of CREB-binding protein (CREBBP) and E1A binding protein p300 (EP300) transcription factors, and reduces histone acetylation on the MMP-9 gene
The critical step for invasion and metastasis is the breakdown of the basement membrane, which requires the activation of proteolytic enzymes, such as MMPs [37, 38]; Previous studies have revealed that downregulation, the activity of MMPs, can provide early targets for preventing cancer metastasis [9, 39]
Summary
Head and neck cancer is a common human cancer, and approximately 50% of cases occur in the oral cavity; more than 90% of these cases involve oral squamous cell carcinoma (OSCC) [1]. Extracellular matrix (ECM) degradation is crucial in cancer invasion and metastasis because the metastasis of cancer cells requires the destruction of mesenchymal collagen or the spreading of the endothelial basement membrane to the surrounding tissue [2]. Inhibition of ECM degradation by proteinases, such as matrix metalloproteinases (MMPs), and plasminogen activators is considered as critical in cancer therapy [3,4,5]. Numerous studies have revealed that MMPs are overexpressed in several types of malignant tumours, including oral cancer [6,7,8]. Of the MMPs, MMP-2 and MMP-9, known as the gelatinases that degrade the main constituent of the basement membrane and type IV collagen, have been recognised as crucial in cancer invasion and metastasis. The detailed effects of melatonin on oral cancer cell metastasis and MMP expression as well as the mechanisms by which these effects occur are still unclear
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