Expression of angiogenic factors is upregulated in hyperplastic mucosa adjacent to colon cancer, and this upregulation is closely associated with cancer growth and metastasis. We investigated the role of histone acetylation in vascular endothelial growth factor (VEGF) expression in hyperplastic mucosa adjacent to orthotopic colon cancer in mice. In the hyperplastic mucosa adjacent to KM12SM tumor in the cecum of athymic mice, VEGF upregulation was associated with hypoxia-inducible factor (HIF)-1alpha induction. The hyperplastic mucosa also showed hypoacetylation of histone H4 and reduction of both p53 and von Hippel-Lindau (VHL) proteins. To examine the effects of growth factors and cytokines on histone acetylation and levels of p53, VHL and HIF-1alpha, the rat intestinal epithelial cell line IEC6 was treated with epidermal growth factor (EGF) and interleukin (IL)-15 for 35 days. Acetylated histone H4, p53 protein and ubiquitinated protein levels were reduced, whereas HIF-1alpha production was upregulated in EGF- and IL-15-treated IEC6 cells. These findings suggest that EGF- or IL-15-induced histone H4 hypoacetylation is associated with repression of p53 and VHL genes in intestinal epithelial cells. The subsequent suppression of protein ubiquitination leads to upregulation of VEGF production by HIF-1alpha retention.
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