Abstract
Chromatin acetylation is attributed with distinct functional relevance with respect to gene expression in normal and diseased conditions thereby leading to a topical interest in the concept of epigenetic modulators and therapy. We report here the identification and characterization of the acetylation inhibitory potential of an important dietary flavonoid, luteolin. Luteolin was found to inhibit p300 acetyltransferase with competitive binding to the acetyl CoA binding site. Luteolin treatment in a xenografted tumor model of head and neck squamous cell carcinoma (HNSCC), led to a dramatic reduction in tumor growth within 4 weeks corresponding to a decrease in histone acetylation. Cells treated with luteolin exhibit cell cycle arrest and decreased cell migration. Luteolin treatment led to an alteration in gene expression and miRNA profile including up-regulation of p53 induced miR-195/215, let7C; potentially translating into a tumor suppressor function. It also led to down-regulation of oncomiRNAs such as miR-135a, thereby reflecting global changes in the microRNA network. Furthermore, a direct correlation between the inhibition of histone acetylation and gene expression was established using chromatin immunoprecipitation on promoters of differentially expressed genes. A network of dysregulated genes and miRNAs was mapped along with the gene ontology categories, and the effects of luteolin were observed to be potentially at multiple levels: at the level of gene expression, miRNA expression and miRNA processing.
Highlights
Reversible histone acetylation has been recognised as a key epigenetic modification for the regulation of gene expression
We identified that the structurally related apigenin does not inhibit p300 activity which could be ascribed to their differential binding on to the p300 HAT domain
Several studies on cancer models both as cell lines and tumours have investigated the effect of luteolin on angiogenesis and it has been shown that luteolin downregulates VEGF expression [32]
Summary
Reversible histone acetylation has been recognised as a key epigenetic modification for the regulation of gene expression. One of the most important natural source derived KATi is CTK7A, a water soluble derivative of curcumin which exhibited tumour regression ability in oral cancer xenograft model system [3] These natural source-derived and modified KATi and several other synthetic KATi such as lysyl CoA [4] and C646 [5] have shown tremendous potential in several preclinical studies, most of these are limited by their working concentrations or their apparent difficulties to be metabolized. All these shortcomings have resulted in an ongoing effort to identify better and efficient molecules with improved therapeutic index
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