Regulation of EP receptors in non-small cell lung cancer by epigenetic modifications

Gray, Steven G., Al-Sarraf, Nael, Baird, Anne-Marie, Cathcart, Mary-Clare, McGovern, Eilish, & O'Byrne, Kenneth J. (2009) Regulation of EP receptors in non-small cell lung cancer by epigenetic modifications. European Journal of Cancer, 45(17), pp. 3087-3097.

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Abstract

Background: Cyclooxygenase (COX)-2 is frequently overexpressed in non-small cell lung cancer (NSCLC) and results in increased levels of prostaglandin E2 (PGE 2), an important signalling molecule implicated in tumourigenesis. PGE 2 exerts its effects through the E prostanoid (EP) receptors (EPs1-4). Methods: The expression and epigenetic regulation of the EPs were evaluated in a series of resected fresh frozen NSCLC tumours and cell lines.

Results: EP expression was dysregulated in NSCLC being up and downregulated compared to matched control samples. For EPs1, 3 and 4 no discernible pattern emerged. EP2 mRNA however was frequently downregulated, with low levels being observed in 13/20 samples as compared to upregulation in 5/20 samples examined. In NSCLC cell lines DNA CpG methylation was found to be important for the regulation of EP3 expression, the demethylating agent decitabine upregulating expression. Histone acetylation was also found to be a critical regulator of EP expression, with the histone deacteylase inhibitors trichostatin A, phenylbutyrate and suberoylanilide hydroxamic acid inducing increased expression of EPs2-4. Direct chromatin remodelling was demonstrated at the promoters for EPs2-4.

Conclusions: These results indicate that EP expression is variably altered from tumour to tumour in NSCLC. EP2 expression appears to be predominantly downregulated and may have an important role in the pathogenesis of the disease. Epigenetic regulation of the EPs may be central to the precise role COX-2 may play in the evolution of individual tumours. © 2009 Elsevier Ltd. All rights reserved.

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ID Code: 65121
Item Type: Journal Article
Refereed: Yes
Additional URLs:
Keywords: Chromatin, Epigenetics, Methylation, Non-small cell lung cancer, Prostanoid, 5 aza 2' deoxycytidine, antineoplastic agent, arylbutyric acid derivative, histone, messenger RNA, prostaglandin E receptor, prostaglandin e receptor 1, prostaglandin E receptor 2, prostaglandin E receptor 3, prostaglandin E receptor 4, trichostatin A, unclassified drug, vorinostat, acetylation, article, cancer cell culture, chromatin assembly and disassembly, controlled study, CpG island, DNA methylation, DNA modification, frozen section, gene expression regulation, human, human cell, human tissue, lung adenocarcinoma, lung non small cell cancer, priority journal, protein expression, receptor down regulation, receptor upregulation, squamous cell carcinoma, Antineoplastic Agents, Azacitidine, Carcinoma, Non-Small-Cell Lung, Cell Proliferation, CpG Islands, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Histone Deacetylase Inhibitors, Histones, Humans, Hydroxamic Acids, Lung Neoplasms, Phenylbutyrates, Receptors, Prostaglandin E, RNA, Messenger, Tumor Cells, Cultured
DOI: 10.1016/j.ejca.2009.09.006
ISSN: 0959-8049
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2009 Pergamon
Deposited On: 05 Dec 2013 00:45
Last Modified: 29 Jul 2014 23:50

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