title: Alpha-keto acid metabolites of organoselenium compounds inhibit histone deacetylase activity in human colon cancer cells.
abstract: Methylselenocysteine (MSC) and selenomethionine (SM) are two organoselenium compounds receiving interest for their potential anticancer properties. These compounds can be converted to beta-methylselenopyruvate (MSP) and alpha-keto-gamma-methylselenobutyrate (KMSB), alpha-keto acid metabolites that share structural features with the histone deacetylase (HDAC) inhibitor butyrate. We tested the organoselenium compounds in an in vitro assay with human HDAC1 and HDAC8; whereas SM and MSC had little or no activity up to 2 mM, MSP and KMSB caused dose-dependent inhibition of HDAC activity. Subsequent experiments identified MSP as a competitive inhibitor of HDAC8, and computational modeling supported a mechanism involving reversible interaction with the active site zinc atom. In human colon cancer cells, acetylated histone H3 levels were increased during the period 0.5-48 h after treatment with MSP and KMSB, and there was dose-dependent inhibition of HDAC activity. The proportion of cells occupying G(2)/M of the cell cycle was increased at 10-50 microM MSP and KMSB, and apoptosis was induced, as evidenced by morphological changes, Annexin V staining and increased cleaved caspase-3, -6, -7, -9 and poly(adenosine diphosphate-ribose)polymerase. P21WAF1, a well-established target gene of clinically used HDAC inhibitors, was increased in MSP- and KMSB-treated colon cancer cells at both the messenger RNA and protein level, and there was enhanced P21WAF1 promoter activity. These studies confirm that in addition to targeting redox-sensitive signaling molecules, alpha-keto acid metabolites of organoselenium compounds alter HDAC activity and histone acetylation status in colon cancer cells, as recently observed in human prostate cancer cells.
authors.affiliation: Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Nian
authors.forename: William H
authors.initials: WH
authors.lastname: Bisson
authors.forename: Wan-Mohaiza
authors.initials: WM
authors.lastname: Dashwood
authors.forename: John T
authors.initials: JT
authors.lastname: Pinto
authors.forename: Roderick H
authors.initials: RH
authors.lastname: Dashwood
mesh_terms: D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D007651:Keto Acids / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D007651:Keto Acids; D016566:Organoselenium Compounds; D012333:RNA, Messenger; D012097:Repressor Proteins; D008156:Luciferases; C110550:HDAC1 protein, human; C409470:HDAC8 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases