MT1G hypermethylation is associated with higher tumor stage in prostate cancer

Purpose: Zinc is involved in several physiologic processes, including cell growth and proliferation. Although in normal prostate tissue zinc levels are high, there is a marked decrease in prostate cancer. Metallothioneins control the bioavailability of zinc and one isoform, MT1G, was reported down-regulated in prostate cancer. Here, we investigated whether promoter methylation might cause MT1G silencing in prostate cancer. Patients and Methods: The MT1G promoter was assessed by quantitative methylation-specific PCR on prospectively collected tissue samples from 121 patients with prostate cancer, 39 paired high-grade prostatic intraepithelial neoplasias (HGPIN), 29 patients with benign prostatic hyperplasia, 13 normal prostate tissue samples from cystoprostatectomy specimens, and prostate cancer cell lines. The methylation levels were calculated and were correlated with clinical and pathologic variables. Reverse transcription-PCR was done in cell lines to assess MT1G mRNA expression before and after demethylating treatment. Results: MT1G promoter hypermethylation was found in 29 of 121 prostate cancer, 5 of 39 HGPIN, 3 of 29 benign prostatic hyperplasia, and 0 of 13 normal prostate tissue samples. No significant differences in methylation frequencies or levels were found (P = 0.057, for both). Methylation levels were found to correlate with tumor stage but not with Gleason grade. MT1G hypermethylation was more frequent in prostate cancer that spread beyond the prostate capsule. All prostate cancer cell lines tested showed MT1G promoter methylation, but no differences in expression were apparent after demethylation. Conclusions: Our findings suggest that MT1G promoter methylation is associated with tumor aggressiveness in prostate cancer and it might be a marker of locally advanced disease.