Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells.
Genistein is a phytoestrogen that has been reported to suppress the AKT signaling pathway in several malignancies. However, the molecular mechanism of genistein action is not known. We tested the hypothesis that genistein activates expression of several aberrantly silenced tumor suppressor genes (TSGs) that have unmethylated promoters such as PTEN, CYLD, p53 and FOXO3a. We report here that genistein activates TSGs through remodeling of the heterochromatic domains at promoters in prostate cancer cells by modulating histone H3-Lysine 9 (H3-K9) methylation and deacetylation. Genistein activation involved demethylation and acetylation of H3-K9 at the PTEN and the CYLD promoter, while acetylation of H3-K9 at the p53 and the FOXO3a promoter occurred through reduction of endogenous SIRT1 activity. There was a decrease of SIRT1 expression and accumulation of SIRT1 in the cytoplasm from the nucleus. Increased expression of these TSGs was also reciprocally related to attenuation of phosphorylated-AKT and NF-kappaB binding activity in prostate cancer cells. This is the first report describing a novel epigenetic pathway that activates TSGs by modulating either histone H3-Lysine 9 (H3-K9) methylation or deacetylation at gene promoters leading to inhibition of the AKT signaling pathway. These findings strengthen the understanding of how genistein may be chemoprotective in prostate cancer.
Kikuno
Nobuyuki
N
Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, CA 94121, USA.
Shiina
Hiroaki
H
Urakami
Shinji
S
Kawamoto
Ken
K
Hirata
Hiroshi
H
Tanaka
Yuichiro
Y
Majid
Shahana
S
Igawa
Mikio
M
Dahiya
Rajvir
R
D000107:Acetylation / Q000187:drug effects; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D002867:Chromones / Q000494:pharmacology; D018899:CpG Islands / Q000187:drug effects; D000077209:Decitabine; D000074749:Deubiquitinating Enzyme CYLD; D015536:Down-Regulation / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor / Q000187:drug effects*; D016158:Genes, p53 / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology*; D006657:Histones / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D008745:Methylation / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048789:Phytoestrogens / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D016588:Anticarcinogenic Agents; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D002867:Chromones; D000077209:Decitabine; D000074749:Deubiquitinating Enzyme CYLD; D004791:Enzyme Inhibitors; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D019833:Genistein; D006657:Histones; D006877:Hydroxamic Acids; D009025:Morpholines; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048789:Phytoestrogens; D047428:Protein Kinase Inhibitors; D056564:Sirtuin 1; D037761:Sirtuins; D025521:Tumor Suppressor Proteins; C499517:FOXO3 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C012589:trichostatin A; C494929:PTEN protein, human; C409984:CYLD protein, human; C447939:SIRT1 protein, human