Prostacyclin synthase expression and epigenetic regulation in nonsmall cell lung cancer

Abstract

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 ¼ .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. Cancer 2011;117:5121-32.

IL-23 is pro-proliferative, epigenetically regulated and modulated by chemotherapy in non-small cell lung cancer

“…However, we also observed a significant increase in a protein which has the correct expected size for IL-23A (20 kDa). These results indicate that post-translational regulation of protein may also be occurring, similar to effects we previously observed for prostacyclin synthase in NSCLC [32]. In this regard IL-23A may be post-translationally modified upon maturation, in a manner similar to IL-6, and IL-12 where glycosylation is a frequent event [33].…”

Perspectives on epigenetic-based immune intervention for rheumatic diseases

“…These findings raise the issue that HDACi may have potentially 'good' and 'bad' effects within the autoimmune disease setting, particularly with regard to pro-inflammatory cytokines. However, we and others have also shown that epigenetic targeting agents have the ability to affect the stability of both expressed mRNAs and proteins [80], and this effect has also been observed in RA, in which HDACi significantly reduced the stability of IL-6 mRNA in FLSs and macrophages [81]. …”

Molecular signatures of ovarian diseases: Insights from network medicine perspective

“…For example, ceramide leads to apoptosis whereas sphingosine-1-phosphate leads to cell survival [Gatt and Dagan 2012]. Prostaglandin I2 is a metabolite of the arachidonic acid pathway and high levels of prostaglandins were reported in peritoneal fluids of endometriosis patients [Cathcart et al 2011;Meresman and Olivares 2012]. Selenomethionine has been identified as a probable agent that can be used in prostate cancers to inhibit, delay, or reverse carcinogenesis [Nyman et al 2004].…”