Mahanine restores RASSF1A expression by down-regulating DNMT1 and DNMT3B in prostate cancer cells

Molecular Cancer

Research

Soumik Agarwal¹  Partha P Banerjee¹  Karishma S Amin¹  Shankar Jagadeesh²  Paruchuri G Rao³  Nabin C Barua³  Gokul Baishay³  Samir Bhattacharya⁴ 

[1] Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, 20057, Washington, DC, USA;Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, 20057, Washington, DC, USA;ACell, Inc, Columbia, MD, USA;Natural Product Chemistry Division, North-East Institute of Science & Technology, 785006, Jorhat, Assam, India;Natural Product Chemistry Division, North-East Institute of Science & Technology, 785006, Jorhat, Assam, India;Cellular and Molecular Endocrinology Laboratory, Centre for Advanced Studies in Zoology, School of Life Science, Visva-Bharati University, 731235, Santiniketan, India;

关键词: Epigenetic silencing;    RASSF1A;    Tumor suppressor gene;    DNMTs;    Prostate cancer;   

DOI  :  10.1186/1476-4598-12-99

 received in 2013-05-22, accepted in 2013-08-24,  发布年份 2013

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Agarwal et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.