Prostacyclin synthase expression and epigenetic regulation in nonsmall cell lung cancer
Cathcart, Mary Clare, Gray , Steven G., Baird, Anne-Marie, Boyle, Elaine, Gately, Kathy, Kay, Elaine, Cummins, Robert, Pidgeon, Graham P., & O'Byrne, Kenneth J. (2011) Prostacyclin synthase expression and epigenetic regulation in nonsmall cell lung cancer. Cancer, 117(22), pp. 5121-5132.
BACKGROUND: Prostacyclin synthase (PGIS) metabolizes prostaglandin H(2), into prostacyclin. This study aimed to determine the expression profile of PGIS in nonsmall cell lung cancer (NSCLC) and examine potential mechanisms involved in PGIS regulation.
METHODS: PGIS expression was examined in human NSCLC and matched controls by reverse transcriptase polymerase chain reaction (RT-PCR), Western analysis, and immunohistochemistry. A 204-patient NSCLC tissue microarray was stained for PGIS and cyclooxygenase 2 (COX2) expression. Staining intensity was correlated with clinical parameters. Epigenetic mechanisms underpinning PGIS promoter expression were examined using RT-PCR, methylation-specific PCR, and chromatin immunoprecipitation analysis.
RESULTS: PGIS expression was reduced/absent in human NSCLC protein samples (P <.0001), but not mRNA relative to matched controls. PGIS tissue expression was higher in squamous cell carcinoma (P =.004) and in male patients (P <.05). No significant correlation of PGIS or COX2 expression with overall patient survival was observed, although COX2 was prognostic for short-term (2-year) survival (P <.001). PGIS mRNA expression was regulated by DNA CpG methylation and histone acetylation in NSCLC cell lines, with chromatin remodeling taking place directly at the PGIS gene. PGIS mRNA expression was increased by both demethylation agents and histone deacetylase inhibitors. Protein levels were unaffected by demethylation agents, whereas PGIS protein stability was negatively affected by histone deacetylase inhibitors.
CONCLUSIONS: PGIS protein expression is reduced in NSCLC, and does not correlate with overall patient survival. PGIS expression is regulated through epigenetic mechanisms. Differences in expression patterns between mRNA and protein levels suggest that PGIS expression and protein stability are regulated post-translationally. PGIS protein stability may have an important therapeutic role in NSCLC. © 2011 American Cancer Society.
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|Item Type:||Journal Article|
|Keywords:||chromatin, histone, methylation, nonsmall cell lung cancer, prostacyclin synthase, survival, azacitidine, bortezomib, cycloheximide, cyclooxygenase 2, messenger RNA, trichostatin A, article, chromatin assembly and disassembly, controlled study, correlation analysis, CpG island, deacetylation, DNA methylation, enzyme activity, enzyme localization, enzyme regulation, epigenetics, female, histone acetylation, human, human cell, human tissue, lung non small cell cancer, major clinical study, male, nucleotide sequence, oncogene, oncological parameters, overall survival, PGIS gene, priority journal, prognosis, protein blood level, protein degradation, protein expression, protein function, protein processing, protein stability, protein targeting, regulatory mechanism, sex ratio, squamous cell carcinoma, survival rate, survival time, Adenocarcinoma, Adult, Aged, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Cytochrome P-450 Enzyme System, Epigenesis, Genetic, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Intramolecular Oxidoreductases, Lung Neoplasms, Middle Aged|
|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 2011 John Wiley & Sons, Inc.|
|Deposited On:||27 Nov 2013 07:34|
|Last Modified:||29 Jul 2014 23:59|
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