Journal Article

Reversal of epigenetic silencing of AP-2alpha results in increased zinc uptake in DU-145 and LNCaP prostate cancer cells

Peter B. Makhov, Konstantin V. Golovine, Alexander Kutikov, Daniel J. Canter, Vera A. Rybko, Dmitry A. Roshchin, Vsevolod B. Matveev, Robert G. Uzzo and Vladimir M. Kolenko

in Carcinogenesis

Volume 32, issue 12, pages 1773-1781
Published in print December 2011 | ISSN: 0143-3334
Published online September 2011 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgr212
Reversal of epigenetic silencing of AP-2alpha results in increased zinc uptake in DU-145 and LNCaP prostate cancer cells

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Zinc accumulation is lost during prostate carcinogenesis. Recent studies reveal a strong association between prostate cancer progression and the downregulation of the zinc uptake transporters hZip1 and hZip3. The aim of this work was to assess the involvement of epigenetic processes in the disruption of zinc uptake homeostasis in prostate adenocarcinoma. In this report, we demonstrate an increase in hZip1 and hZip3 zinc transporters’ expression and zinc uptake by the prostate cancer cells DU-145 and LNCaP in response to 5-aza-2′-deoxycytidine. This effect is due to demethylation of the promoter region of the activator protein (AP)-2alpha protein, which is crucial for hZip1 and hZip3 genes expression. Loss of AP-2alpha expression in DU-145 and LNCaP prostate cancer cells is due to hypermethylation of its promoter region. Similarly, we found higher AP-2alpha promoter methylation levels in clinical samples of early-stage prostate adenocarcinoma when compared with adjacent non-malignant prostate tissue. Taken together, our findings provide a better understanding of the epigenetic mechanisms that are involved in the loss of AP-2alpha protein in prostate cancer cells which lead to decreased cellular zinc uptake—a sine qua non of prostate cancer development.

Journal Article.  6375 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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