The role of epigenetic modifications in retinoic acid receptor beta 2 geneexpression in human prostate cancers

The retinoic acid receptor (RAR) beta gene is a putative tumor suppressor g ene on chromosome 3p24, where a high incidence of loss of heterozygosity is detected in many types of tumors. Retinoic acid suppresses cancer cell gro wth through binding to RARs, especially RAR beta, indicating a critical rol e in mediating anticancer effects. Selective loss or down-regulation of RAR beta mRNA and protein has been reported in prostate cancers (PCas), althou gh the mechanisms remain unclear. We investigated the role of epigenetic mo dification in RAR beta2 gene silencing. Aberrant methylation was detected i n 11 of 14 (79%) primary PCas. 9 of 10 (90%) hormone-refractory PCas, and 2 of 4 (50%) PCa cell lines, but not in any normal prostate samples. Chromat in immunoprecipitation assay showed that all RAR beta2-negative cells (LNCa P, PC3, and DU145) were hypoacetylated at both histones H3 and H4. After ex posure to 5-aza-2 ' -deoxycytidine treatment, Trichostatin A and all-trans retinoic acid induced partial demethylation, increased accumulation of acet ylated histones, and markedly restored the expression of RAR beta2 in RAR b eta2-negative cells. These data suggest that the RAR beta2 gene may be one of the frequently silenced genes by epigenetic modifications in PCa.