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Molecules 2017, 22(1), 62; doi:10.3390/molecules22010062

A Novel Role of Silibinin as a Putative Epigenetic Modulator in Human Prostate Carcinoma

1
Department of Molecular Biology and Genetics, Democritus University of Thrace, University Campus, Dragana, 68100 Alexandroupolis, Greece
2
Redox Biology Center, School of Veterinary Medicine & Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
3
Department of Applied Sciences, Northumbria University, Newcastle Upon Tyne NE1 8ST, UK
4
Department of Pharmaceutical Sciences, College of Science & Technology, Biomanufacturing Research Institute and Technology Enterprise (BRITE), North Carolina Central University, Durham, NC 27707, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Tung-Hu Tsai
Received: 30 November 2016 / Accepted: 22 December 2016 / Published: 31 December 2016
(This article belongs to the Special Issue Silymarin)
View Full-Text   |   Download PDF [3763 KB, uploaded 31 December 2016]   |  

Abstract

Silibinin, extracted from milk thistle (Silybum marianum L.), has exhibited considerable preclinical activity against prostate carcinoma. Its antitumor and chemopreventive activities have been associated with diverse effects on cell cycle, apoptosis, and receptor-dependent mitogenic signaling pathways. Here we hypothesized that silibinin’s pleiotropic effects may reflect its interference with epigenetic mechanisms in human prostate cancer cells. More specifically, we have demonstrated that silibinin reduces gene expression levels of the Polycomb Repressive Complex 2 (PRC2) members Enhancer of Zeste Homolog 2 (EZH2), Suppressor of Zeste Homolog 12 (SUZ12), and Embryonic Ectoderm Development (EED) in DU145 and PC3 human prostate cancer cells, as evidenced by Real Time Polymerase Chain Reaction (RT-PCR). Furthermore immunoblot and immunofluorescence analysis revealed that silibinin-mediated reduction of EZH2 levels was accompanied by an increase in trimethylation of histone H3 on lysine (Κ)-27 residue (H3K27me3) levels and that such response was, in part, dependent on decreased expression levels of phosphorylated Akt (ser473) (pAkt) and phosphorylated EZH2 (ser21) (pEZH2). Additionally silibinin exerted other epigenetic effects involving an increase in total DNA methyltransferase (DNMT) activity while it decreased histone deacetylases 1-2 (HDACs1-2) expression levels. We conclude that silibinin induces epigenetic alterations in human prostate cancer cells, suggesting that subsequent disruptions of central processes in chromatin conformation may account for some of its diverse anticancer effects. View Full-Text
Keywords: silibinin; EZH2; PRC2; histone methylation; H3K27me3; DNMT; HDAC; epigenetics; prostate cancer silibinin; EZH2; PRC2; histone methylation; H3K27me3; DNMT; HDAC; epigenetics; prostate cancer
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Anestopoulos, I.; Sfakianos, A.P.; Franco, R.; Chlichlia, K.; Panayiotidis, M.I.; Kroll, D.J.; Pappa, A. A Novel Role of Silibinin as a Putative Epigenetic Modulator in Human Prostate Carcinoma. Molecules 2017, 22, 62.

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