Histone modification in the TGFbetaRII gene promoter and its significance for responsiveness to HDAC inhibitor in lung cancer cell lines.
We previously reported silencing of the TGF-beta type II receptor gene (TGFbetaRII), involving histone deacetylation, instead of DNA methylation (DNA-Me). Because different histone modifications may play crucial roles in the epigenetic alterations, we further studied links with silencing of the TGFbetaRII gene promoter in six lung cancer cell lines. ChIP assays demonstrated three chromatin patterns for this gene silencing (Pattern I: histone H3 acetylation (H3-Ac)(+/-)/histone H3 lysine 4 methylation (H3K4-Me)(+)/DNA-Me(-), Pattern II; H3-Ac(-)/H3K4-Me(+/-)/DNA-Me(-), and Pattern III; H3-Ac(-)/H3K4-Me(-)/DNA-Me(+)), indicating possible progressive alterations with H3K4-Me alteration. With exposure to a histone deacetylase inhibitor (HDAC-I), trichostatin A, cell lines with the pattern II demonstrated strong and persistent induction of TGFbetaRII expression, while those with the pattern III showed only weak or no induction. ACC-LC-91 cell line, one of the pattern II examples demonstrated strong and continuous induction of H3K4-Me similar to TGFbetaRII expression. In contrast, ACC-LC-176 with the pattern III showed only weak and transient induction of H3K4-Me, similar to TGFbetaRII expression. Treatment with 5-aza-2'-deoxycytidine (5aza-dC) in addition to HDAC-I resulted in strong and continuous induction of TGFbetaRII expression and H3K4-Me in ACC-LC-176, although 5aza-dC alone was without such effects. In ACC-LC-91, both H3-Ac and H3K4-Me were promptly and simultaneously induced by HDAC-I, and similarly inhibited by wortmannin, a PI3K family inhibitor, together with TGFbetaRII induction. These findings suggested progressive alterations of chromatin configuration including H3K4-Me alteration in TGFbetaRII gene silencing. A possible involvement of a wortmannin-sensitive kinase in histone modification was also suggested.
Osada
Hirotaka
H
Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan.
Tatematsu
Yoshio
Y
Sugito
Nobuyoshi
N
Horio
Yoshitsugu
Y
Takahashi
Takashi
T
D000107:Acetylation; D000730:Androstadienes / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology; D002843:Chromatin / Q000378:metabolism; D019175:DNA Methylation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D008239:Lysine; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D000730:Androstadienes; D002843:Chromatin; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; C012589:trichostatin A; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D008239:Lysine; D001374:Azacitidine; D000077191:Wortmannin