Altered Histone Acetylation and Gene Expression in Cancer

Wataru Yasui

Histone acetylation and chromatin remodeling linked with CpG island methylation play a major role in epigenetic regulation of gene expression. Acetylation of histories through histone acetyltransferases and deacetylases disrupts nucleosome structure that leads to DNA relaxation and subsequent increase in accessibility for transcription factors. By Western blotting using anti-acetylated histone H4, the level of acetylated histone H4 expression was obviously reduced in a majority of gastrointestinal cancers in comparison with non-neoplastic mucosa, indicating hypoacetylation status. Immunohistochemical analysis revealed that whereas acetylated histone H4 was uniformly expressed in the nuclei of non-neoplastic epithelial and stromal cells, the expression of acetylated histone H4 was reduced in 70-80% of gastrointestinal carcinomas and 30-40% of adenomas. Furthermore, hypoacetylation status of historic H4 was associated with depth of tumor invasion and nodal metastasis. The histone deacetylase inhibitor trichostatin A (TSA) increases historic acetylation, inhibits cell growth, and induces apoptosis of various human cancers, including oral and gastric cancer cell lines. TSA induced the expression of p21, CBP, Bak, and cyclin E but reduced the expression of E2F-1, E2F4, HDAC-1, and the phosphorylated form of Rb protein. In addition to these cell cycle regulators and apoptosis-related molecules, DNA microarray analysis demonstrated that TSA modulated the expression of various genes related to invasion and metastasis, such as amphiregulin, nm23, matrix metalloproteinase 1, interleukin 8, integrin beta-4, and vascular endothelial growth factor C. Histone acetylation of the promoter region was confirmed by chromatin immunoprecipitation. These findings suggest that historic deacetylation may participate in tumorigenesis, invasion, and metastasis through modulation of the expression of cell cycle regulators and apoptosis-/angiogenesis-/matrix degradation-related genes. Serial analysis of gene expression will uncover novel target genes for histone acetylation in cancers.