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 | Hui Nian, William H Bisson, Wan-Mohaiza Dashwood, John T Pinto, Roderick H Dashwood |
Journal | Carcinogenesis
(Carcinogenesis)
Vol. 30
Issue 8
Pg. 1416-23
(Aug 2009)
ISSN: 1460-2180 [Electronic] England |
PMID | 19528666
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
|
Chemical References |
- Cyclin-Dependent Kinase Inhibitor p21
- Histone Deacetylase Inhibitors
- Histones
- Keto Acids
- Organoselenium Compounds
- RNA, Messenger
- Repressor Proteins
- Luciferases
- HDAC1 protein, human
- HDAC8 protein, human
- Histone Deacetylase 1
- Histone Deacetylases
|
Topics |
- Acetylation
(drug effects)
- Apoptosis
(drug effects)
- Cell Cycle
(drug effects)
- Chromatin Immunoprecipitation
- Colonic Neoplasms
(enzymology, pathology)
- Cyclin-Dependent Kinase Inhibitor p21
(genetics, metabolism)
- Dose-Response Relationship, Drug
- Enzyme-Linked Immunosorbent Assay
- Flow Cytometry
- Histone Deacetylase 1
- Histone Deacetylase Inhibitors
- Histone Deacetylases
(metabolism)
- Histones
(metabolism)
- Humans
- Immunoblotting
- In Situ Nick-End Labeling
- Keto Acids
(pharmacology)
- Luciferases
(metabolism)
- Organoselenium Compounds
(pharmacology)
- Promoter Regions, Genetic
- RNA, Messenger
(genetics, metabolism)
- Repressor Proteins
(antagonists & inhibitors, metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
- Tumor Cells, Cultured
|