Hypermethylation of the prostacyclin synthase (PTGIS) promoter is a frequent event in colorectal cancer and associated with aneuploidy

Frigola, Jordi; Muñoz, Mar; Clark, Susan J.; Moreno, Vı́ctor; Capellà, Gabriel; Peinado, Miguel A.

doi:10.1038/sj.onc.1208883

Cited by 49 publications

(35 citation statements)

References 18 publications

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“…Recently, several papers have examined the role of PGIS promoter VNTR variations and methylation in colorectal cancer (32,33). Results comparable with our PGIS studies of murine and human lung cancer have been observed in a murine model and human colorectal cancer.…”

Section: Discussionsupporting

confidence: 74%

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Genetic and Epigenetic Regulation of the Human Prostacyclin Synthase Promoter in Lung Cancer Cell Lines

Stearman

Grady

Nana‐Sinkam

et al. 2007

Molecular Cancer Research

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The importance of the arachidonic acid pathway has been established in colon and lung cancers, as well as in inflammatory diseases. In these diseases, prostacyclin I 2 (PGI2) and prostaglandin E 2 (PGE2) are thought to have antagonistic activities, with PGI2 exerting anti-inflammatory and antiproliferative activities, whereas PGE2 is proinflammatory and antiapoptotic. In human lung cancer, prostacyclin synthase (PGIS) and PGI2 are down-regulated, whereas PGE2 synthase (PGES) and PGE2 are up-regulated. Murine carcinogenesis models of human lung cancer reciprocate the relationship between PGIS and PGES expression. PGIS-overexpressing transgenic mice are protected from carcinogen-and tobacco smoke -induced lung tumor formation, suggesting that PGI2 may play a role in chemoprevention. We investigated several potential mechanisms for the down-regulation of PGIS in human lung cancer. Using transcription reporter assays, we show that single nucleotide polymorphisms in the PGIS promoter can affect transcriptional activity. In addition, PGIS expression in several human lung cancer cell lines is silenced by CpG methylation, and we have mapped these sites across the variable number of tandem repeats (VNTR) sequence in the promoter, as well as CpGs within exon 1 and the first intron. Finally, using fluorescence in situ hybridization, we show that human lung cancer cell lines and lung cancer tissues do not have a loss of the PGIS genomic region but multiple copies. These results show that an individual's PGIS promoter haplotype can play an important role in the predisposition for lung cancer and CpG methylation provides an epigenetic mechanism for the down-regulated PGIS expression. (Mol Cancer Res 2007;5(3):295 -308)

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Section: Discussionsupporting

confidence: 74%

“…33). In addition, Frigola et al (32) described the hypermethylation of the CpG dinucleotides in the PGIS promoter in colorectal cancer. Seven colon cancer cell lines were hypermethylated, and there was no detectable PGIS mRNA expression in the four lines tested.…”

Section: Discussionmentioning

confidence: 99%

Genetic and Epigenetic Regulation of the Human Prostacyclin Synthase Promoter in Lung Cancer Cell Lines

Stearman

Grady

Nana‐Sinkam

et al. 2007

Molecular Cancer Research

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“…In addition, hypoxia and a constitutively active form of HIF-1␣ markedly induces COX-1 and PGIS expression in endothelial cells (4) and up-regulates PGI 2 production in the ischemic brain (26), which suggests a positive feedback regulation of HIF-1␣ and an important role of PGI 2 under hypoxia. Moreover, although PGI 2 may stabilize the HIF-1␣ in the endothelial cells of tumors under ischemia and enhance angiogenesis, the PGIS promoter was shown to be hypermethylated and its expression suppressed in colorectal cancers and cell lines (34), therefore the function of PGI 2 in tumorigenesis remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Stabilization of Hypoxia-inducible Factor-1α by Prostacyclin under Prolonged Hypoxia via Reducing Reactive Oxygen Species Level in Endothelial Cells

Tzu-Ching

Huang

Tam

et al. 2005

Journal of Biological Chemistry

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Hypoxia-inducible factor-1 (HIF-1) takes part in the transcriptional activation of hypoxia-responsive genes. HIF-1␣, a subunit of HIF-1, is rapidly degraded under normoxic conditions by the ubiquitin-proteosome system. Hypoxia up-regulates HIF-1␣ by inhibiting its degradation, thereby allowing it to accumulate to high levels with 3-6 h of hypoxia treatment and decreasing thereafter. In vascular tissues, prostacyclin (prostaglandin I 2 (PGI 2 )) is a potent vasodilator and inhibitor of platelet aggregation and is known as a vasoprotective molecule. However, the role of PGI 2 in HIF-1 activation has not been studied. In the present study, we investigated the effect of PGI 2 on HIF-1 regulation in human umbilical vein endothelial cells under prolonged hypoxia (12 h). Augmentation of PGI 2 via adenovirus-mediated gene transfer of both cyclooxygenase-1 and PGI 2 synthase activated HIF-1 by stabilizing HIF-1␣ in cells under prolonged hypoxia or the hypoxia-normoxia transition but not under normoxia. Exogenous H 2 O 2 abolished PGI 2 -and catalase-induced HIF-1␣ up-regulation, which suggests that degradation of HIF-1␣ under prolonged hypoxia is through a reactive oxygen species-dependent pathway. Moreover, PGI 2 attenuated NADPH oxidase activity by suppressing Rac1 and p47 phox expression under hypoxia. These data demonstrate a novel function of PGI 2 in down-regulating reactive oxygen species production by attenuating NADPH oxidase activity, which stabilizes HIF-1␣ in human umbilical vein endothelial cells exposed to prolonged hypoxia.Hypoxia induces a number of cellular responses, such as angiogenesis, erythropoiesis, and glycolysis, through both gene regulation and post-translational modification of proteins. Hypoxia-inducible factor-1 (HIF-1) 2 takes part in the transcriptional activation of hypoxia-responsive genes through binding to the hypoxia-responsive element (HRE) in the promoter or enhancer regions and activating a number of genes (1-4). HIF-1 is a heterodimer composed of HIF-1␣ and HIF-1␤. HIF-1␣ is rapidly degraded under normoxic conditions by the ubiquitin-proteosome system, whereas HIF-1␤ is constitutively expressed (5). Under hypoxia, HIF-1␣ has been shown to be up-regulated to high levels at 3-6 h and decrease thereafter (6, 7). A number of studies have focused on the mechanism of HIF-1␣ stabilization under hypoxia for 4 -6 h. Recently, a natural antisense HIF-1␣ was suggested to down-regulate HIF-1␣ in A549 cells under prolonged hypoxia (6). However, regulation of HIF-1␣ under prolonged hypoxia (12 h) in endothelial cells remains largely unknown.Under normoxic conditions, HIF-1␣ is regulated through hydroxylation of proline residues by prolyl hydroxylase enzymes (8, 9). The von Hippel-Lindau tumor suppressor protein (pVHL) associates with hydroxylated HIF-1␣ and targets it for ubiquitination and rapid degradation (10). Under hypoxia, prolyl hydroxylase is inactivated through oxygen-sensing mechanisms, and the unmodified HIF-1␣ accumulates, permitting dimerization with HIF-1␤ (3, 11). Various redox-de...

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“…Inactivation of specific tumor suppressor genes by transcriptional silencing associated with hypermethylation of the promoter is common in cancer. Using reverse transcription-PCR, Frigola et al (26) have shown that PTGIS was inactivated through hypermethylation of its promoter region. Prostacyclin seems to exhibit both antiproliferative effects (27) and chemopreventive properties (28).…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of Peritoneum and Tumor Eicosanoids and Pathways in Advanced Ovarian Cancer

Freedman

Wang²,

Voiculescu³

et al. 2007

Clinical Cancer Research

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Purpose: To describe the eicosanoid profile and differentially expressed eicosanoid and arachidonic acid pathway genes in tissues from patients with advanced epithelial ovarian cancer (EOC). Experimental Design: We first employed electrospray tandem mass spectrometry to determine tissue-specific concentrations of the eicosanoids prostaglandin E 2 (PGE 2 ), the hydroxyeicosatetraenoic acids (12-HETE and 5-HETE), and leukotriene (LTB 4 ), selected for tumor growth potential, and two other bioactive lipids (15-HETE and 13-HODE) with tumor cell proliferation interference potential. The cellular location of eicosanoid activity was identified by immunofluorescence antibody costaining and confocal microscopy. Differential analysis of eicosanoid and arachidonic pathway genes was done using a previously validated cDNA microarray platform. Tissues used included EOC tumor, tumor-free malignant peritoneum (MP), and benign peritoneum (BP) from patients with benign pelvic disease. Results: (a) Eicosanoid products were detected in tumor, MP, and BP specimens. PGE 2 levels were significantly elevated in tumors in an overall comparison with MP or BP (P < 0.001).Combined levels of PGE 2 , 12-HETE, 5-HETE, and LTB 4 increased progressively from low to high concentrations in BP, MP, and tumors (P = 0.012). Neither 15-HETE nor 13-HODE showed a significant opposite trend toward levels found in BP. (b) Tissue specimens representing common EOC histotypes showed strong coexpressions of cyclooxygenases (COX-1) and prostaglandin E synthases (PGES-1) on tumor cells, whereas intratumoral or peritumoral MO/MA coexpressed COX-1 and COX-2 and PGES-1 and PGES-2, respectively. (c) cDNA microarray analysis of MP, BP, and tumor showed that a number of eicosanoid and arachidonic acid pathway genes were differentially expressed in MP and BP compared with tumor, except for CYP2J2, which was increased in tumors. Conclusions: Elevated levels of eicosanoid metabolites in tumors and differential expression of eicosanoid and arachidonic acid pathway genes in the peritoneum support the involvement of bioactive lipids in the inflammatory tumor environment of EOC.Eicosanoids is a collective term for oxygenated derivatives of different 20-carbon fatty acids such as leukotrienes and prostanoids (prostaglandins, prostacyclins, and thromboxanes). These bioactive lipids have important functional roles in regulating many physiologic processes and inflammatory responses (1). Eicosanoid production is a tightly regulated process that depends on (a) the acylation and transfer of arachidonic acid into specific phospholipid pools by arachidonic acid -selective acyltransferase and transacylase reactions and (b) the release of these pools by a variety of phospholipase A 2 (PLA 2 ) enzymes (2).Arachidonic acid liberated by PLA 2 is metabolized by cyclooxygenase (COX) and lipoxygenase (LOX) enzymes variously expressed in cells and tissues, and contribute to the production of specific metabolites (1, 3, 4). These bioactive lipids or eicosanoids then exert their biol...

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Hypermethylation of the prostacyclin synthase (PTGIS) promoter is a frequent event in colorectal cancer and associated with aneuploidy

Cited by 49 publications

References 18 publications

Genetic and Epigenetic Regulation of the Human Prostacyclin Synthase Promoter in Lung Cancer Cell Lines

Genetic and Epigenetic Regulation of the Human Prostacyclin Synthase Promoter in Lung Cancer Cell Lines

Stabilization of Hypoxia-inducible Factor-1α by Prostacyclin under Prolonged Hypoxia via Reducing Reactive Oxygen Species Level in Endothelial Cells

Comparative Analysis of Peritoneum and Tumor Eicosanoids and Pathways in Advanced Ovarian Cancer

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