The Association of Retinoic Acid Receptor Beta2(RARβ2) Methylation Status and Prostate Cancer Risk: A Systematic Review and Meta-Analysis

Abstract

The retinoic acid receptor beta2(RARβ2) is a type of nuclear receptor that is activated by both all-trans retinoic acid and 9-cis retinoic acid, which has been shown to function as a tumor suppressor gene in different types of human tumors. Previous reports demonstrated that the frequency of RARβ2 methylation was significantly higher in prostate cancer patients compared with controls, but the relationship between RARβ2 promoter methylation and pathological stage or Gleason score of prostate cancer remained controversial. Therefore, a meta-analysis of published studies investigating the effects of RARβ2 methylation status in prostate cancer occurrence and association with both pathological stage and Gleason score in prostate cancer was performed in the study. A total of 12 eligible studies involving 777 cases and 404 controls were included in the pooled analyses. Under the random-effects model, the pooled OR of RARβ2 methylation in prostate cancer patients, compared to non-cancer controls, was 17.62 with 95%CI = 6.30–49.28. The pooled OR with the fixed-effects model of pathological stage in RASSF1A methylated patients, compared to unmethylated patients, was 0.67 (95%CI = 0.40–1.09) and the pooled OR of low-GS in RARβ2 methylated patients by the random-effect model, compared to high-GS RARβ2 methylated patients, was 0.54 (95%CI = 0.28–1.04). This study showed that RARβ2 might be a potential biomarker in prostate cancer prevention and diagnosis. The detection of RARβ2 methylation in urine or serum is a potential non-invasive diagnostic tool in prostate cancer. The present findings also require confirmation through adequately designed prospective studies.

Association of folate and other one-carbon related nutrients with hypermethylation status and expression of RARB, BRCA1, and RASSF1A genes in breast cancer patients

“…The methylation of CpGs in the P2 promoter sequence of RARB is usually addressed to epigenetically influence its transcription [3,19,28]. This region (containing an Sp1 element) is amplified by MSP and entails a major and appropriate number of CpGs which could be analyzed by the methylationspecific and nonspecific primers represented in Table 1 [3,12,28,29].…”

“…There is also convincing evidence of tissue and gene specificity of hypermethylated genes in association with plasma folate in specific malignancies, such as colorectal cancer (CRC) [9,13,18]. The preferential modulation of regional methylation through which dietary methyl donor components can selectively influence the gene expression remains to be illuminated [9,19].…”

Epigenetic basis of cancer health disparities: Looking beyond genetic differences

“…AR signaling, central to prostate cancer progression [77], is known to be epigenetically regulated [78]. The tumor suppressor RARβ2 , similar to its hypermethylation in breast cancer [54, 79], cervical cancer [53] and leukemia [80], is significantly more hypermethylated in prostate cancer patients, and correlates with increased tumor risk [81]. Role of SPARC has been investigated in multiple cancer models [82] and its function largely depends on whether it is produced by cancer cells or the stromal cells in the tumor microenvironment [82].…”

Epigenetics Territory and Cancer

“…These findings suggest that epigenetic silencing of miR-9 loci constitutes an important event in breast carcinogenesis. In an study, Xu et al (2013) found that DNMT1 expression, which is aberrantly upregulated in breast cancer and its overexpression is responsible for the hypermethylation of miR-148a and miR-152 promoters, and is inversely correlated with the expression levels of miR-148a/152 in breast cancer tissues; suggesting a negative feedback regulatory loop between miR-148a/152 and DNMT1 in breast cancer (Xu et al 2013). Interestingly, upon treatment of the breast cancer cells with a DNA demethylating agent, reduced tumor growth and inhibition of metastasis were also documented through the reactivation of miR-148.…”