Oncotarget

Research Papers:

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

Ruthrotha B. Selvi, Amrutha Swaminathan, Snehajyoti Chatterjee, Muthu K. Shanmugam, Feng Li, Gowsica B. Ramakrishnan, Kodappully Sivaraman Siveen, Arunachalam Chinnathambi, M. Emam Zayed, Sulaiman Ali Alharbi, Jeelan Basha, Akshay Bhat, Madavan Vasudevan, Arunasalam Dharmarajan, Gautam Sethi and Tapas K. Kundu _

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Oncotarget. 2015; 6:43806-43818. https://doi.org/10.18632/oncotarget.6245

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Abstract

Ruthrotha B. Selvi1, Amrutha Swaminathan1, Snehajyoti Chatterjee1, Muthu K. Shanmugam2, Feng Li2, Gowsica B. Ramakrishnan1, Kodappully Sivaraman Siveen2, Arunachalam Chinnathambi3, M. Emam Zayed3, Sulaiman Ali Alharbi3, Jeelan Basha1, Akshay Bhat1, Madavan Vasudevan4, Arunasalam Dharmarajan5, Gautam Sethi2,3,5 and Tapas K. Kundu1

1 Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Jakkur, Bangalore, India

2 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

3 Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia

4 Bionivid Technology [P] Ltd, East of NGEF, Bangalore, India

5 School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Curtin University, Bentley, Western Australia, Australia

Correspondence to:

Tapas K. Kundu, email:

Keywords: flavonoids, miRNA, gene expression, cancer

Received: May 22, 2015 Accepted: October 14, 2015 Published: October 26, 2015

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.


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