SUV39H1-mediated DNMT3A is participated in the epigenetic regulation of Tim-3 and galectin-9 in cervical cancer

Abstract Background: Methylation of histone 3 at lysine 9 (H3K9) and DNA methylation are among the most highly conserved epigenetic marks that correlate well with gene 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. Methods: The methylation status of HAVCR2 and LGALS9 was detected by MS-PCR in cervical cancer tissues and cell lines. The underlying molecular mechanisms 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. Results: Here, we show that SUV39H1 up-regulates H3K9me3 expression in DNMT3A promoter region, which in turn induced expression of DNMT3A. In addition, our 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 in the DNMT3A promoter region was found to correlate with Tim-3 and galectin-9 expression at the cellular level，indicating that SUV39H1-H3K9me3-DNMT3A is a crucial regulatory axis in cervical cancer. Conclusion: These results indicate that SUV39H1-DNMT3A is a crucial Tim-3 and galectin-9 regulatory axis in cervical cancer.