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Epigenetic Regulation Of Zinc Transport In Prostate Cancer
David A Kunkle*, Peter Makhov*, Konstantin Golovine*, Vladimir M Kolenko*, Robert G Uzzo
Fox Chase Cancer Center, Temple University Hospital, Philadelphia, PA
Introduction: Prostate carcinogenesis involves transformation of normal zinc-accumulating cells to malignant cells which do not accumulate zinc. Clinically, cancer cells with higher levels of zinc demonstrate less malignant behavior. In tumors, hypermethylation of CPG islands or acetylation of nucleosome histones may cause gene silencing or enhanced gene expression, respectively. We investigated epigenetic regulation of zinc levels and expression of hZIP1 and hZIP2 zinc uptake transporters in prostate cancer cells.
Methods: DU-145 and PC-3 prostate cancer cell lines were cultured in medium alone or in the presence of the demethylating agent 5-aza-2’-deoxycytidine(dAza) and/or the histone deacetylase inhibitor Trichostatin-A(TSA). hZIP1 and hZIP2 expression was evaluated by quantitative real-time PCR. Zinc accumulation was monitored by flow cytometry using the zinc-specific indicator FluoZin-3. Promoter sequences for hZIP1 and hZIP2 genes were determined using online software. Methylation status was determined by bisulphate DNA sequencing.
Results: Prostate cancer cells treated with dAza and TSA exhibited significantly up-regulated expression of hZIP1 and hZIP2 transport proteins and increased intracellular zinc accumulation. While sequencing revealed no methylated CG sites inside hZIP1 promoters, 3/5 sites within the hZIP2 promoter were methylated. Treatment with dAza and TSA was shown to increase histone acetylation of hZIP1 and hZIP2 promoters while decreasing methylation.
Conclusions: Loss of the unique ability to maintain intracellular zinc levels may be important in development and progression of prostate cancer. Our results demonstrate that epigenetic mechanisms may directly or indirectly regulate zinc uptake genes. These findings may support the development of novel strategies for therapeutic interventions in prostate cancer.
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