The Role of Epigenetic Modifications in Retinoic Acid Receptor β2 Gene Expression in Human Prostate Cancers

Abstract

SUMMARY: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 RAR␤2 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 RAR␤2-negative cells (LNCaP, PC3, and DU145) were hypoacetylated at both histones H3 and H4. After exposure to 5-aza-2'-deoxycytidine treatment, Trichostatin A and all-trans retinoic acid induced partial demethylation, increased accumulation of acetylated histones, and markedly restored the expression of RAR␤2 in RAR␤2-negative cells. These data suggest that the RAR␤2 gene may be one of the frequently silenced genes by epigenetic modifications in PCa. (Lab Invest 2001, 81:1049 -1057.

MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumours

“…Retinoic acid receptor-b2, a known tumour suppressor gene, which has been shown to be silenced in PC-3 cells (Nakayama et al, 2001). N-(2-aminophenyl)4-[N-(pyridine-3-yl-methoxy-carbonyl) aminomethyl]benzamide has previously been shown to reactivate RARb2 in a variety of cell lines including prostate, renal carcinoma and breast cancer cells (Hess-Stumpp et al, 2007).…”

“…Increased acetylation of H3 and H4 is especially important because cells that are RARb negative (LNCaP, PC-3 and DU-145 PCa cell lines) have been shown to be hypoacetylated at H3 and H4 (Nakayama et al, 2001). This is another reason why combining an HDACI with a RAMBA is especially important for PCa treatment.…”

“…Histone deacetylase inhibitors have been reported to have growth inhibitory activities in PCa models both in vitro and in vivo (Butler et al, 2000;Nakayama et al, 2001;Gediya et al, 2005). In addition, HDACIs when combined with retinoids (e.g., ATRA, 9-cis retinoic acid (9-CRA) or 13-cis-retinoic acid (13-CRA)) display enhanced (additive) anticancer activities (Pili et al, 2001;Gediya et al, 2005;Qian et al, 2005Qian et al, , 2007.…”

Methylation of the retinoid response gene TIG1 in prostate cancer correlates with methylation of the retinoic acid receptor beta gene

“…Epigenetic inactivation of tumor suppressor genes through DNA methylation in CpGrich promoter regions contributes to tumorigenesis (Baylin and Herman, 2000;Jones and Baylin, 2002). In prostate cancer, aberrant methylation is involved in the inactivation of various important genes such as E-cadherin, CD44, RASSF1A, GSTP1, the endothelin B receptor, p16, the androgen receptor gene, the retinoic acid receptor beta (RARbeta), the estrogen receptor beta (ER-beta) and the caveolin-1 gene (Lee et al, 1994;Nelson et al, 1997;Cui et al, 2001;Kito et al, 2001;Li et al, 2000Li et al, , 2001Nakayama et al, 2001;Pao et al, 2001;Kuzmin et al, 2002;Liu et al, 2002). When tested, loss of the expression of these genes was associated with CpG island hypermethylation, and expression could be restored after treatment with 5-aza-2 0 -deoxycytidine (5-Aza-CdR), a DNA methyltransferase inhibitor.…”

Identification of differentially methylated CpG islands in prostate cancer

“…4 In prostate cancers, inactivation by aberrant methylation has been reported for many genes, such as RAR␤2, GST-P, E-cadherin and RASSF1A. [5][6][7][8] Methylation profiling analysis of multiple genes has been proposed for the purpose of evaluating biologic characteristics and identifying useful diagnostic indicators of prognosis. 9 As methods for determining genes with expression regulated by DNA methylation, restriction landmark genomic scanning (RLGS), methylated CpG island amplification (MCA)/representational difference analysis (RDA) and differential methylation hybridization (DMH) have been reported.…”