Data from Hypermethylation of the <i>GABRE∼miR-452∼miR-224</i> Promoter in Prostate Cancer Predicts Biochemical Recurrence after Radical Prostatectomy

Abstract

<div>Abstract<p><b>Purpose:</b> Available tools for prostate cancer diagnosis and prognosis are suboptimal and novel biomarkers are urgently needed. Here, we investigated the regulation and biomarker potential of the <i>GABRE∼miR-452∼miR-224</i> genomic locus.</p><p><b>Experimental Design:</b> GABRE/miR-452/miR-224 transcriptional expression was quantified in 80 nonmalignant and 281 prostate cancer tissue samples. <i>GABRE∼miR-452∼miR-224</i> promoter methylation was determined by methylation-specific qPCR (MethyLight) in 35 nonmalignant, 293 prostate cancer [radical prostatectomy (RP) cohort 1] and 198 prostate cancer tissue samples (RP cohort 2). Diagnostic/prognostic biomarker potential of <i>GABRE∼miR-452∼miR-224</i> methylation was evaluated by ROC, Kaplan–Meier, uni- and multivariate Cox regression analyses. Functional roles of miR-224 and miR-452 were investigated in PC3 and DU145 cells by viability, migration, and invasion assays and gene-set enrichment analysis (GSEA) of posttransfection transcriptional profiling data.</p><p><b>Results:</b><i>GABRE∼miR-452∼miR-224</i> was significantly downregulated in prostate cancer compared with nonmalignant prostate tissue and had highly cancer-specific aberrant promoter hypermethylation (AUC = 0.98). Functional studies and GSEA suggested that miR-224 and miR-452 inhibit proliferation, migration, and invasion of PC3 and DU145 cells by direct/indirect regulation of pathways related to the cell cycle and cellular adhesion and motility. Finally, in uni- and multivariate analyses, high <i>GABRE∼miR-452∼miR-224</i> promoter methylation was significantly associated with biochemical recurrence in RP cohort 1, which was successfully validated in RP cohort 2.</p><p><b>Conclusion:</b> The <i>GABRE∼miR-452∼miR-224</i> locus is downregulated and hypermethylated in prostate cancer and is a new promising epigenetic candidate biomarker for prostate cancer diagnosis and prognosis. Tumor-suppressive functions of the intronic miR-224 and miR-452 were demonstrated in two prostate cancer cell lines, suggesting that epigenetic silencing of <i>GABRE∼miR-452∼miR-224</i> may be selected for in prostate cancer. <i>Clin Cancer Res; 20(8); 2169–81. ©2014 AACR</i>.</p></div>