Histone acetylation and gastrointestinal carcinogenesis.
The importance of altered histone acetylation in gastrointestinal carcinogenesis, especially in relation to invasion and metastasis, is described. Histone acetylation and chromatin remodeling linked with CpG island methylation play a major role in epigenetic regulation of gene expression. Acetylation of histones through an imbalance of histone acetyltransferases and deacetylases disrupts nucleosome structure, which leads to DNA relaxation and subsequent increase in accessibility to transcription factors. The expression of acetylated histone H4 is reduced in a majority of gastric and colorectal cancers, indicating the low level of global histone acetylation in tumor cells. Moreover, reduced histone acetylation is significantly associated with depth of tumor invasion and nodal metastasis of gastrointestinal cancers. A histone deacetylase inhibitor, trichostatin A (TSA), induces growth arrest and apoptosis and suppresses invasion of cancer cells. Treatment with TSA, which is followed by increased histone acetylation in the promoters, induces the expression of many genes that are suppressors of invasion and metastasis, including tissue inhibitors of metalloproteinase and nm23H1/H2, in addition to negative cell cycle regulators and apoptosis-related molecules. Our approach, serial analysis of gene expression (SAGE), enabled us to identify a gene that is a novel candidate for a metastasis suppressor, whose expression is induced by histone acetylation. These findings suggest that, by modifying gene expression, histone deacetylation may participate not only in tumorigenesis but also in invasion and metastasis. Therefore, histone acetylation should be a promising target for cancer therapy, especially against invasive and metastatic disease, but also for cancer prevention.
Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical Sciences, Kasumi, Minami-ku, Hiroshima 734-8551, Japan. wyasui@hiroshima-u.ac.jp
Wataru
W
Yasui
Naohide
N
Oue
Shigehiro
S
Ono
Yoshitsugu
Y
Mitani
Reiko
R
Ito
Hirofumi
H
Nakayama
D000107:Acetylation; D002455:Cell Division; D018899:CpG Islands; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000517:prevention & control
D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A