Butyrate, an HDAC inhibitor, stimulates interplay between different posttranslational modifications of histone H3 and differently alters G1-specific cell cycle proteins in vascular smooth muscle cells.
HDACs and HATs regulate histone acetylation, an epigenetic modification that controls chromatin structure and through it, gene expression. Butyrate, a dietary HDAC inhibitor, inhibits VSMC proliferation, a crucial factor in atherogenesis, and the principle mechanism in arterial and in-stent restenosis. Here, the link between antiproliferation action of butyrate and the portraits of global covalent modifications of histone H3 that it induces are characterized to understand the mechanics of butyrate-arrested VSMC proliferation. Analysis of histone H3 modifications specific to butyrate arrested VSMC proliferation display induction of histone H3-Lysine9 acetylation, inhibition of histone H3-Serine10 phosphorylation, reduction of histone H3-Lysine9 dimethylation and stimulation of histone H3-Lysine4 di-methylation, which is linked to transcriptional activation, cell cycle/mitosis, transcriptional suppression and activation, respectively. Conversely, untreated VSMCs exhibit inhibition of H3-Lysine9 acetylation, induction of H3-Serine10 phosphorylation, stimulation of H3-Lysine9 di-methylation and reduction in H3-Lysine4 di-methylation. Butyrate's cooperative effects on H3-Lysine9 acetylation and H3-Serine10 phosphorylation, and contrasting effects on di-methylation of H3-Lysine9 and H3-Lysine4 suggests that the interplay between these site-specific modifications cause distinct chromatin alterations that allow cyclin D1 and D3 induction, G1-specific cdk4, cdk6 and cdk2 downregulation, and upregulation of cdk inhibitors, p15INK4b and p21Cip1. Regardless of butyrate's effect on D-type cyclins, downregulation of G1-specific cdks and upregulation of cdk inhibitors by butyrate prevents cell cycle progression by failing to inactivate Rb. Overall, through chromatin remodeling, butyrate appears to differentially alter G1-specific cell cycle proteins to ensure proliferation arrest of VSMCs, a crucial cellular component of blood vessel wall.
Department of Pharmaceutical Sciences, College of Pharmacy, Texas Southern University, 3100, Cleburne Street, Houston, Texas 77004, USA.
Omana P
OP
Mathew
Kasturi
K
Ranganna
Frank M
FM
Yatsu
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics; D002087:Butyrates / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051381:Rats; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D002087:Butyrates; D018797:Cell Cycle Proteins; D002843:Chromatin; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D016160:Retinoblastoma Protein; D018844:Cyclin-Dependent Kinases