Retinoic acid receptor β2 is epigenetically silenced either by DNA methylation or repressive histone modifications at the promoter in cervical cancer cells

To elucidate the silencing mechanism of retinoic acid receptor β2 (RARβ2) in cervical carcinogenesis, we investigated RARβ2 expression and the status of both DNA methylation and histone modifications at the promoter in cervical cancer cell lines. RARβ2 was frequently repressed in cancer cell lines and in primary cancers of the cervix. Although the majority of RARβ2-negative cancers had methylated promoter, RARβ2 was repressed with hypomethylated promoter in a substantial fraction of the cancers. The RARβ2-negative cells with hypomethylated promoters showed a repressive histone modification pattern at the promoter. RARβ2 was reactivated by a histone deacetylase inhibitor, accompanied by formation of active histone modifications. The repressive modification was also observed in cells repressed with hypermethylated promoter, but RARβ2 was reactivated only by DNA demethylating agent and not by histone deacetylase inhibitor. Our results suggest that RARβ2 is silenced by either of the two key epigenetic pathways, DNA methylation or repressive histone modifications, depending on the individual cancer cells.