Histone deacetylase (
HDAC) inhibitors are gaining interest as
cancer therapeutic agents. We tested the hypothesis that natural
organoselenium compounds might be metabolized to
HDAC inhibitors in human
prostate cancer cells. Se-Methyl-L-
selenocysteine (MSC) and
selenomethionine are
amino acid components of
selenium-enriched yeast. In a cell-free system,
glutamine transaminase K (GTK) and
L-amino acid oxidase convert MSC to the corresponding alpha-keto
acid, beta-methylselenopyruvate (MSP), and
L-amino acid oxidase converts
selenomethionine to its corresponding alpha-keto
acid, alpha-keto-gamma-methylselenobutyrate (KMSB). Although
methionine (
sulfur analogue of
selenomethionine) is an excellent substrate for GTK,
selenomethionine is poorly metabolized. Structurally, MSP and KMSB resemble the known
HDAC inhibitor butyrate. We examined
androgen-responsive LNCaP cells and
androgen-independent LNCaP C4-2, PC-3, and DU145 cells and found that these human
prostate cancer cells exhibit endogenous GTK activities. In the corresponding cytosolic extracts, the metabolism of MSC was accompanied by the concomitant formation of MSP. In MSP-treated and KMSB-treated
prostate cancer cell lines, acetylated
histone 3 levels increased within 5 hours, and returned to essentially baseline levels by 24 hours, suggesting a rapid, transient induction of
histone acetylation. In an in vitro HDAC activity assay, the selenoamino
acids, MSC and
selenomethionine, had no effect at concentrations up to 2.5 mmol/L, whereas MSP and KMSB both inhibited HDAC activity. We conclude that, in addition to targeting redox-sensitive signaling
proteins and
transcription factors, alpha-keto
acid metabolites of MSC and
selenomethionine can alter HDAC activity and
histone acetylation status. These findings provide a potential new paradigm by which naturally occurring organoselenium might prevent the progression of human
prostate cancer.