Novel property of Se-methyl-L-selenocysteine as a histone deacetylase inhibitor in human prostate cancer cells.

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Studies show that histone deacetylase (HDAC) inhibitors disrupt the cell cycle and/or induce apoptosis and that cancer cells appear to be more sensitive than non-transformed cells. With the knowledge that epidemiological studies support a protective role of organoselenium against development of prostate cancer, we hypothesize that Se-methyl-L-selenocysteine (MSC), a component of selenium-enriched yeast, is metabolized to an HDAC inhibitor and regulates proliferative and/or apoptotic responses in human prostate cancer cells. An aminotransferase (glutamine transaminase K) and L-amino acid oxidase convert MSC to the corresponding α-keto acid (β-methylselenopyruvate, BMS) in a cell-free system. Both enzymes also catalyze a β-elimination side reaction yielding pyruvate, ammonium and methylselenol. BMS structurally resembles the HDAC inhibitor, butyrate, but with the potential redox action of selenium targeting a zinc-thiolate ligand in the active site. To test our hypothesis, both androgen responsive (LNCaP) and androgen independent (C4-2, PC-3 and DU145) prostate cancer cells were cultured for various time intervals in medium supplemented with MSC. Acetylated histones (as evidence of HDAC inhibition) and HDAC activity were measured in nuclear and cytosolic fractions. Results show that nuclear expression of acetylated histone 3 was significantly increased by 24-h in all MSC-treated cell lines, demonstrating the attenuation of HDAC activity. By contrast, MSC itself had no direct HDAC inhibitory activity in nuclear extracts (LNCaP, C4-2, PC-3 and DU145), suggesting that a metabolite(s) of MSC, rather than MSC itself, inhibits HDAC activity in prostate cancer cells. HPLC analysis of cytosolic extracts incubated with MSC in a transamination reaction mixture with α-keto-γ-methiolbutyrate showed metabolism of MSC with concomitant formation of a transaminase product, tentatively identified as BMS. In addition to a transamination product, a β-elimination product (methylselenol) may also contribute to control of prostate cancer progression. MSC and/or its metabolite(s) down-regulate the levels of Redox Factor-1 and NF-κB, redox sensitive proteins that affect cellular proliferative and apoptotic responses. This study demonstrates a previously unrecognized effect of MSC as an HDAC inhibitor in addition to targeting redox-sensitive signaling proteins and transcription factors and adds a new understanding to mechanisms by which naturally-occurring organoselenium prevents progression of human prostate cancer. Supported by NCI RO1 CA11184 and NIH R01 ES08421.