Down-regulation of the progesterone receptor by the methylation of progesterone receptor gene in endometrial cancer cells.

Progesterone plays an important role in the regulation of normal endometrium function by binding to progesterone receptor (PR). In endometrial cancer, however, PR is always down-regulated. Previous reports showed that methylation in the promoter region of the PR gene may be responsible for PRB isoform repression. However, the CpG islands in the exon region of the PR gene are much richer and longer than in the promoter region. We hypothesize that methylation in the exon region may also take part in the down-regulation of the PR gene. The methylation status of the first exon of the PR gene in endometrial cell cultures was investigated. Aberrant methylation patterns were observed in the first exon of PR gene, and the methylation density is correlated with the differentiation of different types of endometrial cancer cells. DNA methyltransferase (DNMT) and histone deacetylase inhibitor 5-aza-2'-deoxycytidine (ADC), as well as trichostatin A (TSA), which reverses PR gene expression, were also studied. A combination of ADC and TSA resulted in synergistic effects in inducing PR expression, down-regulation of DNMT1 and DNMT3A, and could also have antigrowth effect on endometrial cancer cells by inducing apoptosis.