[No authors listed]
Persistent infection with highârisk human papillomavirus is known to cause cervical cancer. The binding of the costimulatory factors, Timâ3 and galectinâ9, can cause immune tolerance and lead to immune escape during carcinogenesis. Epigenetic regulation is essential for Timâ3/galectinâ9 expression, which affects the outcome of local cervical cancer infection. Hence, exploring the epigenetic regulatory mechanisms of costimulatory signaling by Timâ3/galectinâ9 is of great interest for investigating the mechanisms through which these proteins are regulated in cervical cancer tumorigenesis. In this study, we report that E2Fâ1 and FOXM1 mediated by HPV18 E6 and E7 can enhance the transcriptional activity of Enhancer of zeste homolog 2 (EZH2) by binding to its promoter region, resulting in the induced expression of the EZH2âspecific target protein, H3K27me3, which consequently reduces the expression of the downstream target gene, DNA (cytosineâ5)âmethyltransferase 3A (DNMT3A). EZH2 and H3K27me3 directly interact with the DNMT3A promoter region to negatively regulate its expression in HeLa cells. Moreover, the downregulated DNMT3A and the decreased methylation levels in HAVCR2/LGALS9 promoter regions in HeLa cells promoted the expression of Timâ3/galectinâ9. Furthermore, the high expression of Timâ3/galectinâ9 was associated with HPV positivity among patients with cervical cancer. Moreover, HAVCR2/LGALS9 promoter regions were hypermethylated in normal cervical tissues, and this hypermethylated status inhibited gene expression. On the whole, these findings suggest that EZH2, H3K27me3 and DNMT3A mediate the epigenetic regulation of the negative stimulatory molecules, Timâ3 and galectinâ9 in cervical cancer which is associated with HPV18 infection.
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