Carcinogenesis Advance Access published online on June 15, 2009
Carcinogenesis, doi:10.1093/carcin/bgp147
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
-Keto acid metabolites of organoselenium compounds inhibit histone deacetylase activity in human colon cancer cells
1 Department of Biochemistry & Biophysics, Oregon State University, Corvallis OR 97331
2 Linus Pauling Institute, Oregon State University, Corvallis, OR 97331
3 Department of Biochemistry & Molecular Biology, New York Medical College, Valhalla, NY 10595
4 Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, OR 97331
* To whom correspondence should be addressed. Tel: +1 541 737 5086; Fax: +1 541 737 5077; Email: Rod.Dashwood{at}oregonstate.edu
Methylselenocysteine (MSC) and selenomethionine (SM) are two organoselenium compounds receiving interest for their potential anti-cancer properties. These compounds can be converted to β-methylselenopyruvate (MSP) and 
-keto-
-methylselenobutyrate (KMSB), -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 G2/M of the cell cycle was increased at 10-50 µM 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(ADP-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 mRNA and protein level, and there was enhanced P21WAF1 promoter activity. These studies confirm that in addition to targeting redox-sensitive signaling molecules, -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.
Key Words: chemoprevention • apoptosis • p21 • acetylated histones • epigenetics
Received March 13, 2009; revised June 8, 2009; accepted June 9, 2009.