Abstract
BackgroundMethylation of histone 3 at lysine 9 (H3K9) and DNA methylation are epigenetic marks correlated with genes silencing. The tumor microenvironment significantly influences therapeutic responses and clinical outcomes. The epigenetic-regulation mechanism of the costimulatory factors Tim-3 and galectin-9 in cervical cancer remains unknown.MethodsThe methylation status of HAVCR2 and LGALS9 were detected by MS-PCR in cervical cancer tissues and cell lines. The underlying molecular mechanism of SUV39H1-DNMT3A-Tim-3/galectin-9 regulation was elucidated using cervical cancer cell lines containing siRNA or/and over-expression system. Confirmation of the regulation of DNMT3A by SUV39H1 used ChIP-qPCR.ResultsSUV39H1 up-regulates H3K9me3 expression at the DNMT3A promoter region, which in turn induced expression of DNMT3A in cervical cancer. In addition, the mechanistic studies indicate that DNMT3A mediates the epigenetic modulation of the HAVCR2 and LGALS9 genes by directly binding to their promoter regions in vitro. Moreover, in an in vivo assay, the expression profile of SUV39H1 up-regulates the level of H3K9me3 at the DNMT3A promoter region was found to correlate with Tim-3 and galectin-9 cellular expression level.ConclusionThese results indicate that SUV39H1-DNMT3A is a crucial Tim-3 and galectin-9 regulatory axis in cervical cancer.
Highlights
Methylation of histone 3 at lysine 9 (H3K9) and DNA methylation are epigenetic marks correlated with genes silencing
Tim‐3 and galectin‐9 expression were increased due to genes methylation level decreased in cervical cancer Using the Oncomine databases, the mRNA expression levels of HAVCR2 and LGALS9 were compared between cervical cancer and normal cervical samples
The results indicated that the expression levels of HAVCR2 and LGALS9 were all higher in cervical cancer than in normal cervical samples (Fig. 1a, b)
Summary
Methylation of histone 3 at lysine 9 (H3K9) and DNA methylation are epigenetic marks correlated with genes silencing. The epigenetic-regulation mechanism of the costimulatory factors Tim-3 and galectin-9 in cervical cancer remains unknown. DNA methylation is participated in gene expression changes that occur in cervical cancer [10]. Our previous study revealed that EZH2H3K27me3-DNMT3A mediates the epigenetic regulation of the negative stimulatory molecules, Tim-3 and galectin-9 in cervical cancer which is associated with HPV18 infection [11]. Trimethylation of histone 3 lysine 9 (H3K9me3) at gene promoter regions is an important epigenetic mechanism that silences genes expression [12, 13] and SUV39H1 is H3K9me3-specific histone methyltransferase [14]
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