Mahanine restores RASSF1A expression by down-regulating DNMT1 and DNMT3B in prostate cancer cellsReportar como inadecuado




Mahanine restores RASSF1A expression by down-regulating DNMT1 and DNMT3B in prostate cancer cells - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Molecular Cancer

, 12:99

First Online: 30 August 2013Received: 22 May 2013Accepted: 24 August 2013DOI: 10.1186-1476-4598-12-99

Cite this article as: Agarwal, S., Amin, K.S., Jagadeesh, S. et al. Mol Cancer 2013 12: 99. doi:10.1186-1476-4598-12-99

Abstract

BackgroundHypermethylation of the promoter of the tumor suppressor gene RASSF1A silences its expression and has been found to be associated with advanced grade prostatic tumors. The DNA methyltransferase DNMT family of enzymes are known to be involved in the epigenetic silencing of gene expression, including RASSF1A, and are often overexpressed in prostate cancer. The present study demonstrates how mahanine, a plant-derived carbazole alkaloid, restores RASSF1A expression by down-regulating specific members of the DNMT family of proteins in prostate cancer cells.

ResultsUsing methylation-specific PCR we establish that mahanine restores the expression of RASSF1A by inducing the demethylation of its promoter in prostate cancer cells. Furthermore, we show that mahanine treatment induces the degradation of DNMT1 and DNMT3B, but not DNMT3A, via the ubiquitin-proteasome pathway; an effect which is rescued in the presence of a proteasome inhibitor, MG132. The inactivation of Akt by wortmannin, a PI3K inhibitor, results in a similar down-regulation in the levels DNMT1 and DNMT3B. Mahanine treatment results in a decline in phospho-Akt levels and a disruption in the interaction of Akt with DNMT1 and DNMT3B. Conversely, the exogenous expression of constitutively active Akt inhibits the ability of mahanine to down-regulate these DNMTs, suggesting that the degradation of DNMT1 and DNMT3B by mahanine occurs via Akt inactivation.

ConclusionsTaken together, we show that mahanine treatment induces the proteasomal degradation of DNMT1 and DNMT3B via the inactivation of Akt, which facilitates the demethylation of the RASSF1A promoter and restores its expression in prostate cancer cells. Therefore, mahanine could be a potential therapeutic agent for advanced prostate cancer in men when RASSF1A expression is silenced.

KeywordsEpigenetic silencing RASSF1A Tumor suppressor gene DNMTs Prostate cancer Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-12-99 contains supplementary material, which is available to authorized users.

Soumik Agarwal, Karishma S Amin contributed equally to this work.

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Autor: Soumik Agarwal - Karishma S Amin - Shankar Jagadeesh - Gokul Baishay - Paruchuri G Rao - Nabin C Barua - Samir Bhattacha

Fuente: https://link.springer.com/







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