Inhibition of p300 lysine acetyltransferase activity by luteolin reduces tumor growth in head and neck squamous cell carcinoma (HNSCC) xenograft mouse model

Selvi, Ruthrotha B and Swaminathan, Amrutha and Chatterjee, Snehajyoti and Shanmugam, Muthu K and Li, Feng and Ramakrishnan, Gowsica B and Siveen, Kodappully Sivaraman and Chinnathambi, Arunachalam and Zayed, M. Emam and Alharbi, Sulaiman Ali and Basha, Jeelan and Bhat, Akshay and Vasudevan, Madavan and Dharmarajan, Arunasalam and Sethi, Gautam and Kundu, Tapas K (2016) Inhibition of p300 lysine acetyltransferase activity by luteolin reduces tumor growth in head and neck squamous cell carcinoma (HNSCC) xenograft mouse model. In: ONCOTARGET, 6 (41). pp. 43806-43818.

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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.

Item Type:	Journal Article
Publication:	ONCOTARGET
Publisher:	IMPACT JOURNALS LLC
Additional Information:	Copy right for this article belongs to the IMPACT JOURNALS LLC, 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA
Keywords:	flavonoids; miRNA; gene expression; cancer
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	02 Apr 2016 09:59
Last Modified:	17 Oct 2018 13:19
URI:	http://eprints.iisc.ac.in/id/eprint/53514

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