Abstract
PurposeWe investigated the genomic DNA methylation profile of prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) cancer model and to analyze the crosstalk among targeted genes and the related functional pathways.MethodsProstate DNA samples from 24-week-old TRAMP and C57BL/6 male mice were isolated. The DNA methylation profiles were analyzed by methylated DNA immunoprecipitation (MeDIP) followed by next-generation sequencing (MeDIP-seq). Canonical pathways, diseases and function and network analyses of the different samples were then performed using the Ingenuity® Pathway Analysis (IPA) software. Some target genes with significant difference in methylation were selected for validation using methylation specific primers (MSP) and qPCR.ResultsTRAMP mice undergo extensive aberrant CpG hyper- and hypo-methylation. There were 2147 genes with a significant (log2-change ≥ 2) change in CpG methylation between the two groups, as mapped by the IPA software. Among these genes, the methylation of 1105 and 1042 genes was significantly decreased and increased, respectively, in TRAMP prostate tumors. The top associated disease identified by IPA was adenocarcinoma; however, the cAMP response element-binding protein (CREB)-, histone deacetylase 2 (HDAC2)-, glutathione S-transferase pi (GSTP1)- and polyubiquitin-C (UBC)-related pathways showed significantly altered methylation profiles based on the canonical pathway and network analyses. MSP and qPCR results of genes of interests corroborated with MeDIP-seq findings.ConclusionsThis is the first MeDIP-seq with IPA analysis of the TRAMP model to provide novel insight into the genome-wide methylation profile of prostate cancer. Studies on epigenetics, such as DNA methylation, will potentially provide novel avenues and strategies for further development of biomarkers targeted for treatment and prevention approaches for prostate cancer.
Highlights
IntroductionProstate cancer is the second leading male cancer (accounts for 13.8% of all male cancers) and its prevalence ranking number five among all cancers [1]
Prostate cancer is the second leading male cancer and its prevalence ranking number five among all cancers [1]
The results showed, in Dync1i1 and Slc1a4 genes, the relative density of M-methylation specific primers (MSP) to that of U-MSP in transgenic adenocarcinoma of the mouse prostate (TRAMP) group were increased, which indicated that the CpG sites of these genes were hypermethylated in TRAMP mice (Fig. 4)
Summary
Prostate cancer is the second leading male cancer (accounts for 13.8% of all male cancers) and its prevalence ranking number five among all cancers [1]. In the United States, prostate cancer is the most common. Epigenetic changes include DNA methylation, histone modification, and posttranslational gene regulation by. DNA methylation has been well studied, and aberrant DNA methylation patterns are a characteristic feature of cancer [7,8,9]. The first reported epigenetic changes in human cancer were DNA methylation losses. Hypermethylation of CpG islands (CGIs) at promoters of tumor suppressor genes, homeobox genes and other sequences are other consistent epigenetic features of cancer [12, 13]. CpG island methylator-phenotype (CIMP) tumors have been identified in many cancers, including oral cancer, colorectal cancer [14] and colon cancer [15]. It is worthwhile to profile the global DNA methylation changes between cancer models and controls to elucidate the mechanisms of carcinogenesis
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