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; Tapas K Kundu

doi:10.18632/oncotarget.6245

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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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Peer reviewed

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, …

Oncotarget, Vol.6(41), pp.43806-43818

12/22/2015

DOI: 10.18632/oncotarget.6245

PMCID: PMC4791268

PMID: 26517526

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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.

Animals

Antineoplastic Agents - pharmacology

Carcinoma, Squamous Cell - pathology

Cell Proliferation - drug effects

Chromatin Immunoprecipitation

Flow Cytometry

Head and Neck Neoplasms - pathology

Humans

Immunoblotting

Immunohistochemistry

Luteolin - pharmacology

Lysine - metabolism

Mice

Molecular Docking Simulation

Oligonucleotide Array Sequence Analysis

p300-CBP Transcription Factors - metabolism

Squamous Cell Carcinoma of Head and Neck

Transcriptome - drug effects

Xenograft Model Antitumor Assays

Details

Title: Subtitle: Inhibition of p300 lysine acetyltransferase activity by luteolin reduces tumor growth in head and neck squamous cell carcinoma (HNSCC) xenograft mouse model
Creators: Ruthrotha B Selvi - Jawaharlal Nehru Centre for Advanced Scientific Research
Amrutha Swaminathan - Jawaharlal Nehru Centre for Advanced Scientific Research
Snehajyoti Chatterjee - Jawaharlal Nehru Centre for Advanced Scientific Research
Muthu K Shanmugam - National University of Singapore
Feng Li - National University of Singapore
Gowsica B Ramakrishnan - Jawaharlal Nehru Centre for Advanced Scientific Research
Kodappully Sivaraman Siveen - National University of Singapore
Arunachalam Chinnathambi - King Saud University
M Emam Zayed - King Saud University
Sulaiman Ali Alharbi - King Saud University
Jeelan Basha - Jawaharlal Nehru Centre for Advanced Scientific Research
Akshay Bhat - Jawaharlal Nehru Centre for Advanced Scientific Research
Madavan Vasudevan - Corvid Technologies
Arunasalam Dharmarajan - School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Curtin University, Bentley, Western Australia, Australia
Gautam Sethi - National University of Singapore
Tapas K Kundu - Jawaharlal Nehru Centre for Advanced Scientific Research
Resource Type: Journal article
Publication Details: Oncotarget, Vol.6(41), pp.43806-43818
DOI: 10.18632/oncotarget.6245
PMID: 26517526
PMCID: PMC4791268
NLM abbreviation: Oncotarget
ISSN: 1949-2553
eISSN: 1949-2553
Publisher: Impact Journals LLC
Language: English
Date published: 12/22/2015
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984303858702771

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