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Alpha‐keto acid metabolites of organoselenium compounds inhibit HDAC activity
Author(s) -
Nian Hui,
Dashwood Roderick H
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.894.7
Subject(s) - acetylation , chemistry , histone , biochemistry , in vitro , glutamine , histone deacetylase , apoptosis , cell cycle checkpoint , cancer research , cell cycle , amino acid , biology , gene
HDAC inhibitors are gaining interest as cancer therapeutic agents. We hypothesized that natural organoselenium compound Se‐methylselenocysteine (MSC) might be metabolized to an HDAC inhibitor. In a cell‐free assay, glutamine transaminase K (GTK) converted MSC to methylselenopyruvate (MSP). Molecular modeling supported the interaction of MSP with zinc in the HDAC pocket. In an in vitro HDAC activity assay, MSP was a competitive inhibitor. In various cancer cell lines, MSP increased acetylated histone levels, and induced cell cycle arrest and/or apoptosis. P21WAF1 was increased at both the mRNA and protein level by MSP, and there was enhanced P21WAF1 promoter activity. This work provides a new paradigm by which organoselenium compounds might protect against prostate, colon, skin and other cancers. Thus, in addition to targeting redox‐sensitive signaling molecules, alpha‐keto acid metabolites of organoselenium compounds might alter HDAC activity and histone acetylation status.