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Histone modification in the TGFβRII gene promoter and its significance for responsiveness to HDAC inhibitor in lung cancer cell lines

We previously reported silencing of the TGF‐β type II receptor gene (TGFβRII), 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 TGFβRII 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 TGFβRII 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 TGFβRII expression. In contrast, ACC‐LC‐176 with the pattern III showed only weak and transient induction of H3K4‐Me, similar to TGFβRII expression. Treatment with 5‐aza‐2′‐deoxycytidine (5aza‐dC) in addition to HDAC‐I resulted in strong and continuous induction of TGFβRII 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 TGFβRII induction. These findings suggested progressive alterations of chromatin configuration including H3K4‐Me alteration in TGFβRII gene silencing. A possible involvement of a wortmannin‐sensitive kinase in histone modification was also suggested. © 2005 Wiley‐Liss, Inc.