Selenite reactivates silenced genes by modifying DNA methylation and histones in prostate cancer cells

Abstract

DNA hypermethylation is a common epigenetic alteration in human prostate cancer and is considered to contribute to development of this disease. Accumulating data suggest that dietary factors may alter cancer risk by modifications of epigenetic processes in the cell. The present study was designed to investigate whether selenium (Se) would alter epigenetic events to regulate methylation-silenced genes in human prostate cancer cells. DNA methylation, histone modifications and gene expression were studied in LNCaP cells after selenite treatment using polymerase chain reaction, western blot analysis, chromatin immunoprecipitation assay and enzymatic activity assay. Our study shows that selenite treatment caused partial promoter DNA demethylation and reexpression of the pi-class glutathione-S-transferase (GSTP1) in LNCaP cells in a dose- and time-dependent manner. Selenite treatment decreased messenger RNA levels of DNA methyltransferases (DNMTs) 1 and 3A and protein levels of DNMT1. Selenite also decreased histone deacetylase activity and increased levels of acetylated lysine 9 on histone H3 (H3-Lys 9), but decreased levels of methylated H3-Lys 9. Selenite treatment reduced levels of DNMT1 and methylated H3-Lys 9 associated with the GSTP1 promoter, but increased levels of acetylated H3-Lys 9 associated with this promoter. Additionally, selenite treatment decreased general DNA methylation and caused partial promoter demethylation and reexpression of the tumor suppressor adenomatous polyposis coli and cellular stress response 1, a gene involving tumor growth and metastasis. Our study demonstrates that Se can epigenetically modulate DNA and histones to activate methylation-silenced genes. These epigenetic modifications may contribute to cancer prevention by Se.

Epigenetic effects of selenium and their implications for health

“…31 In line with reduced HDAC activity, the authors found both global and GSTP1 promoter-bound levels of H3K9ac-a repressive mark-to be increased and H3K9me3-an activating mark-to be decreased upon Se treatment. Other studies have confirmed that dietary and synthetic selenocompounds inhibit HDAC activity.…”

“…46 In vivo, a non-significant decrease of DNMT activity was seen in the liver and colon of rats fed Se-adequate vs. -deficient diets (0.2 and 0 mg Se/kg diet as sodium selenite). 28 Similarly, DNMT1 protein expression was diminished by 1.5 mM sodium selenite in rat cardiomyocytes 40 and in LNCaP cells 31 and by 8 mM sodium selenite and 2 mM MSA in MCF-7 cells. 47 The in vitro human and animal studies collectively indicate that Se is inversely associated with global DNA methylation and DNMT activity.…”

“…The change in chromatin structure observed by Arai et al could be caused by global DNA methylation differences in Se-supplemented versus deficient cells. Studies employing rodents [27][28][29][30] and cell lines 31 have 27 and by HPLC detection of 5 mC monophosphate in enzymatically digested DNA. 30 Corresponding data from in vitro studies is limited to one paper, showing that LNCaP prostate tumor cells treated with 1.5 mM selenite for 7 d had a »50% decrease in 5 mC immunoreactivity.…”

“…30 Corresponding data from in vitro studies is limited to one paper, showing that LNCaP prostate tumor cells treated with 1.5 mM selenite for 7 d had a »50% decrease in 5 mC immunoreactivity. 31 A conclusion that can be drawn is that impacts of selenite and SelMet on global DNA methylation are possibly masked by strain-specific effects and that they are also influenced by the nutritional context (e.g., high fat diet). This topic has been elucidated in a human study (N D 287) that found a significant inverse association of plasma Se and global DNA methylation in leukocytes.…”

Environmental chemical stressors as epigenome modifiers: a new horizon in assessment of toxicological effects

“…Dietary selenium may also influence DNA methylation status and further influence disease predisposition, e.g. cancer [57,82,83], by affecting one-carbon metabolism in a different way compared to folate.…”