The Role of Epigenetic Modifications in Retinoic Acid Receptor |[bgr]|2 Gene Expression in Human Prostate Cancers

摘要

The retinoic acid receptor (RAR) gene is a putative tumor suppressor gene on chromosome 3p24, where a high incidence of loss of heterozygosity is detected in many types of tumors. Retinoic acid suppresses cancer cell growth through binding to RARs, especially RAR, indicating a critical role in mediating anticancer effects. Selective loss or down-regulation of RAR mRNA and protein has been reported in prostate cancers (PCas), although the mechanisms remain unclear. We investigated the role of epigenetic modification in RAR2 gene silencing. Aberrant methylation was detected in 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. Chromatin immunoprecipitation assay showed that all RAR2-negative cells (LNCaP, PC3, and DU145) were hypoacetylated at both histones H3 and H4. After exposure to 5-aza-2prime;-deoxycytidine treatment, Trichostatin A and all-trans retinoic acid induced partial demethylation, increased accumulation of acetylated histones, and markedly restored the expression of RAR2 in RAR2-negative cells. These data suggest that the RAR2 gene may be one of the frequently silenced genes by epigenetic modifications in PCa.