Inhibition of p300 lysine acetyltransferase activity by luteolin reduces tumor growth in head and neck squamous cell carcinoma (HNSCC) xenograft mouse model.
Inhibition of p300 lysine acetyltransferase activity by luteolin reduces tumor growth in head and neck squamous cell carcinoma (HNSCC) xenograft mouse model.
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DOI：
10.18632/oncotarget.6245
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发表时间：
2015-12-22
期刊：
影响因子：
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通讯作者：
Kundu TK
中科院分区：
文献类型：
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作者：
Selvi RB;Swaminathan A;Chatterjee S;Shanmugam MK;Li F;Ramakrishnan GB;Siveen KS;Chinnathambi A;Zayed ME;Alharbi SA;Basha J;Bhat A;Vasudevan M;Dharmarajan A;Sethi G;Kundu TK
染色质乙酰化与基因在正常和疾病条件下的表达具有明显的功能相关性，因此引起了人们对表观遗传调节剂和治疗概念的兴趣。我们在此报告了一种重要的膳食类黄酮木犀草素的乙酰化抑制潜力的鉴定和表征。木犀草素通过竞争性结合乙酰辅酶A结合部位来抑制p300乙酰转移酶。在头颈部鳞状细胞癌(HNSCC)的异种移植瘤模型中，木犀草素治疗导致肿瘤生长在4周内显著减少，与组蛋白乙酰化的减少相对应。木犀草素处理的细胞表现出细胞周期停滞和细胞迁移减少。木犀草素治疗导致基因表达和miRNA谱的改变，包括P53诱导的miR-195/215，let7C的上调；潜在地转化为肿瘤抑制功能。它还导致miR-135a等癌基因iRNAs下调，从而反映了microRNA网络的全球变化。此外，通过染色质免疫沉淀对差异表达基因的启动子的抑制，建立了组蛋白乙酰化抑制与基因表达之间的直接关联。随着基因本体论的分类，木犀草素潜在地在多个水平上发挥作用：在基因表达、miRNA表达和miRNA加工水平。
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.