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Histone Acetylation and Gastrointestinal Carcinogenesis
Author(s) -
YASUI WATARU,
OUE NAOHIDE,
ONO SHIGEHIRO,
MITANI YOSHITSUGU,
ITO REIKO,
NAKAYAMA HIROFUMI
Publication year - 2003
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2003.tb05977.x
Subject(s) - cancer research , cancer epigenetics , trichostatin a , histone methyltransferase , histone h4 , acetylation , biology , histone , histone deacetylase 5 , hdac11 , histone deacetylase , histone h2a , ezh2 , hdac4 , histone deacetylase 2 , genetics , gene
A bstract : 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.