Histone modification in the TGFβRII gene promoter and its significance for responsiveness to HDAC inhibitor in lung cancer cell lines
✍ Scribed by Hirotaka Osada; Yoshio Tatematsu; Nobuyoshi Sugito; Yoshitsugu Horio; Takashi Takahashi
- Publisher
- John Wiley and Sons
- Year
- 2005
- Tongue
- English
- Weight
- 335 KB
- Volume
- 44
- Category
- Article
- ISSN
- 0899-1987
- DOI
- 10.1002/mc.20135
No coin nor oath required. For personal study only.
✦ Synopsis
We previously reported silencing of the TGF-b type II receptor gene (TGFbRII), 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 TGFbRII 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)(þ/À)/ histone H3 lysine 4 methylation (H3K4-Me)(þ)/DNA-Me(À), Pattern II; H3-Ac(À)/H3K4-Me(þ/À)/DNA-Me(À), and Pattern III; H3-Ac(À)/H3K4-Me(À)/DNA-Me(þ)), 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 TGFbRII 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 TGFbRII expression. In contrast, ACC-LC-176 with the pattern III showed only weak and transient induction of H3K4-Me, similar to TGFbRII expression. Treatment with 5-aza-2 0 -deoxycytidine (5aza-dC) in addition to HDAC-I resulted in strong and continuous induction of TGFbRII 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 TGFbRII induction. These findings suggested progressive alterations of chromatin configuration including H3K4-Me alteration in TGFbRII gene silencing. A possible involvement of a wortmannin-sensitive kinase in histone modification was also suggested.