Regulation of Chk2 gene expression in lymphoid malignancies: involvement of epigenetic mechanisms in Hodgkin's lymphoma cell lines.
The tumor suppressor Chk2 kinase plays crucial roles in regulating cell-cycle checkpoints and apoptosis following DNA damage. We investigated the expression levels of the genes encoding Chk2 and several cell-cycle regulators in nine cell lines from lymphoid malignancies, including three Hodgkin's lymphoma (HL) lines. We found that all HL cell lines exhibited a drastic reduction in Chk2 expression without any apparent mutation of the Chk2 gene. However, expression of Chk2 in HL cells was restored following treatment with the histone deacetylase inhibitors trichostatin A (TsA) and sodium butyrate (SB), or with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5Aza-dC). Chromatin-immunoprecipitation (Chip) assays revealed that treatment of HL cells with TsA, SB or 5Aza-dC resulted in increased levels of acetylated histones H3 and H4, and decreased levels of dimethylated H3 lysine 9 at the Chk2 promoter. These results indicate that expression of the Chk2 gene is downregulated in HL cells via epigenetic mechanisms.
Kato
N
N
Department of Genome Sciences, Faculty of Medical Sciences, Graduate School of Medicine, Kobe University, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Fujimoto
H
H
Yoda
A
A
Oishi
I
I
Matsumura
N
N
Kondo
T
T
Tsukada
J
J
Tanaka
Y
Y
Imamura
M
M
Minami
Y
Y
D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006689:Hodgkin Disease / Q000235:genetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008223:Lymphoma / Q000235:genetics*; D008745:Methylation; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics
D002087:Butyrates; D006657:Histones; D006877:Hydroxamic Acids; D012333:RNA, Messenger; C012589:trichostatin A; D000077209:Decitabine; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D001374:Azacitidine