title: Inhibition of p300 lysine acetyltransferase activity by luteolin reduces tumor growth in head and neck squamous cell carcinoma (HNSCC) xenograft mouse model.
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.
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Jakkur, Bangalore, India.
authors.forename: Ruthrotha B
authors.initials: RB
authors.lastname: Selvi
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Jakkur, Bangalore, India.
authors.forename: Amrutha
authors.initials: A
authors.lastname: Swaminathan
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Jakkur, Bangalore, India.
authors.forename: Snehajyoti
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Muthu K
authors.initials: MK
authors.lastname: Shanmugam
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Jakkur, Bangalore, India.
authors.forename: Gowsica B
authors.initials: GB
authors.lastname: Ramakrishnan
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Kodappully Sivaraman
authors.initials: KS
authors.lastname: Siveen
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Arunachalam
authors.initials: A
authors.lastname: Chinnathambi
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: M Emam
authors.initials: ME
authors.lastname: Zayed
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Sulaiman Ali
authors.initials: SA
authors.lastname: Alharbi
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Jakkur, Bangalore, India.
authors.forename: Jeelan
authors.initials: J
authors.lastname: Basha
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Jakkur, Bangalore, India.
authors.forename: Akshay
authors.initials: A
authors.lastname: Bhat
authors.affiliation: Bionivid Technology [P] Ltd, East of NGEF, Bangalore, India.
authors.forename: Madavan
authors.initials: M
authors.lastname: Vasudevan
authors.affiliation: School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Curtin University, Bentley, Western Australia, Australia.
authors.forename: Arunasalam
authors.initials: A
authors.lastname: Dharmarajan
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia.|School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Curtin University, Bentley, Western Australia, Australia.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Jakkur, Bangalore, India.
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Kundu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047311:Luteolin / Q000494:pharmacology*; D008239:Lysine / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D020411:Oligonucleotide Array Sequence Analysis; D000077195:Squamous Cell Carcinoma of Head and Neck; D059467:Transcriptome / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D000970:Antineoplastic Agents; D047311:Luteolin; D008239:Lysine; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
keywords: cancer; flavonoids; gene expression; miRNA