CD44 Methylation Levels in Androgen-Deprived Prostate Cancer: A Putative Epigenetic Modulator of Tumor Progression

Epigenetic changes have been reported to promote the development and progression of prostate cancer (PCa). Compared to normal prostate tissue, tumor samples from patients treated with androgen-deprivation therapy (ADT) show the hypermethylation of genes primarily implicated in PCa progression. A series of 90 radical prostatectomies was retrospectively analyzed. A total of 46 patients had undergone surgery alone (non-treated) and 44 had received ADT prior to surgery (treated). Promoter methylation analysis of the candidate genes possibly involved in PCa response to ADT (AR, ESR1, ESR2, APC, BCL2, CD44, CDH1, RASSF1, ZEB1) was conducted by pyrosequencing. The mRNA expression of differentially methylated genes was investigated by quantitative real-time PCR. Intratumoral microvessel density and ERG expression were also assessed using immunohistochemistry. A statistically significant difference in CD44 promoter methylation levels was found, with higher levels in the non-treated cases, which accordingly showed lower CD44 gene expression than the treated cases. Moreover, lower ESR1 methylation levels were associated with higher ERG expression, and the CD44 methylation levels were increased in ERG-overexpressing tumors, particularly in the treated cases. Our data suggest an interplay between ERG expression and the epigenetic modifications in key genes of prostate tumorigenesis, and that CD44 promoter methylation could serve as a promising molecular biomarker of PCa progression under androgen-deprived conditions.