Epigenetic deregulation of the COX pathway in cancer

Progress in Lipid Research 51 (2012) 301–313

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Review

Epigenetic deregulation of the COX pathway in cancer Inês Cebola 1, Miguel A. Peinado ⇑ Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona, Catalonia, Spain

a r t i c l e

i n f o

Article history: Received 2 December 2011 Received in revised form 8 February 2012 Accepted 8 February 2012 Available online 3 May 2012 Keywords: DNA methylation Histone modification Gene regulation Gene silencing Prostaglandins Inflammation and cancer

a b s t r a c t Inflammation is a major cause of cancer and may condition its progression. The deregulation of the cyclooxygenase (COX) pathway is implicated in several pathophysiological processes, including inflammation and cancer. Although, its targeting with nonsteroidal antiinflammatory drugs (NSAIDs) and COX-2 selective inhibitors has been investigated for years with promising results at both preventive and therapeutic levels, undesirable side effects and the limited understanding of the regulation and functionalities of the COX pathway compromise a more extensive application of these drugs. Epigenetics is bringing additional levels of complexity to the understanding of basic biological and pathological processes. The deregulation of signaling and biosynthetic pathways by epigenetic mechanisms may account for new molecular targets in cancer therapeutics. Genes of the COX pathway are seldom mutated in neoplastic cells, but a large proportion of them show aberrant expression in different types of cancer. A growing body of evidence indicates that epigenetic alterations play a critical role in the deregulation of the genes of the COX pathway. This review summarizes the current knowledge on the contribution of epigenetic processes to the deregulation of the COX pathway in cancer, getting insights into how these alterations may be relevant for the clinical management of patients. Ó 2012 Elsevier Ltd. All rights reserved.

Contents 1.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. The COX pathway and cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Epigenetics and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epigenetic alterations of the COX pathway in cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. The cyclooxygenases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Prostaglandin E2 biosynthesis and signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Prostacyclin biosynthesis and signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Prostaglandin D2 biosynthesis and signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Thromboxane A2 biosynthesis and signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Prostaglandin F2a biosynthesis and signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: AKR1B1, aldo–keto reductase family 1 member B1; AOM, azoxymethane; COX, cycloxigenase; COX-1 (also known as PTGS1), cycloxigenase 1; COX-2 (also known as PTGS2), cycloxigenase 2; Coxibs, selective COX-2 inhibitors; CRTH2 (also known as DP2), chemoattractant receptor-homologous expressed on T helper type 2 cells; EP1 (also known as PTGER1), PGE2 receptor 1; EP2 (also known as PTGER2), PGE2 receptor 2; EP3 (also known as PTGER3), PGE2 receptor 3; EP4 (also known as PTGER4), PGE2 receptor 4; HDACs, histone deacetylases; HPGD, 15-hydroxyprostaglandin dehydrogenase; HPGDS (also known as H-PGDS), hematopoietic PGD2 synthase; HPV, human papillomavirus; IP (PTGIR), prostacyclin receptor; LOX, lipoxygenase; MBDs, methyl-binding domain proteins; NSAIDs, nonsteroidal antiinflammatory drugs; PLA2, phospholipase A2; PPAR, peroxisome-proliferator-activated receptor; PGD2, prostaglandin D2; PGE2, prostaglandin E2; PGF2a, prostaglandin F2a; PGH2, prostaglandin H2; PGI2, prostacyclin (also known as prostaglandin I2); PKA, protein kinase A; PTGDR (also known as DP1), prostaglandin D2 receptor; PTGDS (also known as L-PGDS), lipocalin-type PGD2 synthase; PTGES (also known as mPGES-1), microsomal membrane-bound PGE2 synthase-1; PTGES2 (also known as mPGES-2), microsomal membrane-bound PGE2 synthase-2; PTGES3 (also known as cPGES), cytosolic PGE2 synthase 3; PTGFR (also known as FP), PGF2a receptor; PTGIS (also known as PGIS), prostacyclin synthase; TBXAS1 (also known as TXAS), thromboxane synthase; TP (also known as TBXA2R), thromboxane receptor; TXA2, thromboxane A2. ⇑ Corresponding author. Address: Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Camí de les Escoles s/n, 08916 Badalona, Barcelona, Spain. Tel.: +34 93 554 3050; fax: +34 93 465 1472. E-mail address: [email protected] (M.A. Peinado). 1 Present address: Institut d’Investigacións Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Rosselló 153, Edifici CEK, Planta 5, 08036 Barcelona, Spain. 0163-7827/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.plipres.2012.02.005

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1. Introduction Several factors contribute to cancer development and maintenance, including genetic and epigenetic alterations, chronic inflammation and lifestyle factors, such as diet and tobacco smoking. In particular, a large body of evidence from epidemiological and animal model studies demonstrates an association between high-fat diets and increased risk for particular malignant diseases, such as colorectal, pancreatic, breast and prostate cancer [1]. Arachidonic acid is a polyunsaturated fatty acid present in most mammalian cell membranes and a major component of animal fats. Mostly released from the membrane by phospholipase A2 (PLA2), this fatty acid can be substrate for the generation of distinct eicosanoids, being metabolized by the cyclooxygenase (COX) pathway, the lipoxygenase (LOX) pathway or the cytochrome P450 monooxygenase pathway. Several reports show that both COX and LOX pathways are frequently overactivated during chronic inflammation and cancer (reviewed in reference [2]), which may account for the association between high-fat diets and higher incidence of chronic inflammation settings and malignant growths (reviewed in reference [3]). Cyclooxygenases catalyze the two-step conversion reaction of arachidonic acid into prostaglandin H2 (PGH2), which constitutes the precursor for the subsequent synthesis of a number of structurally related prostanoids, the prostaglandins and thromboxanes, by specialized eicosanoid synthases. Importantly, not only the prostanoid production, but the presence of specific G protein-coupled receptors at the cell surface as well, is determining for the establishment of downstream prostanoid-dependent signaling. These

surface receptors are designated according to the concomitant ligand. In addition, prostanoids such as prostacyclin are able to bind nuclear receptors from the peroxisome proliferator-activated receptors family (see below) (Fig. 1). Noteworthy, whereas biosynthesis and receptor binding account for the final outcome of the pathway, maintenance of a given metabolic state implicates influx and efflux transporters, as well as cytoplasmatic inactivation, which may be enzyme-dependent or not.

1.1. The COX pathway and cancer There are two major COX isoforms, COX-1 (also known as PTGS1) and COX-2 (also known as PTGS2). Although the expression profiles of both isoforms are variable from tissue to tissue, COX-1 is generally considered the constitutive form, being responsible for the homeostatic production of prostanoids and highly expressed in most tissues, including platelets, lung, prostate, brain, gastrointestinal tract, kidney, liver and spleen. On the contrary, COX-2, often referred as the inducible or rate-limiting isoform, is usually undetectable in most normal tissues, being responsible for most of the prostanoid production during inflammation and markedly upregulated in various types of cancer, as well as in other diseases [4–7]. However, recent data indicates that the ‘constitutive’ and ‘inducible’ terms may be too reductionist for the complex dynamics of COX-1 versus COX-2. In fact, several normal tissues show detectable COX-2 levels [8]. Moreover, high levels of both COX-1 and COX-2 have been found in mouse lung tumors [9]. A third isoform, COX-3, has been also described, however, it appears to

Fig. 1. Diagram of the COX pathway. Arachidonic acid is a polyunsaturated fatty acid that constitutes the phospholipid domain of most cell membranes and is liberated from the cellular membranes by cytoplasmic phospholipase A2 (PLA2). Free arachidonic acid can be metabolized to eicosanoids through three major pathways: the cyclooxygenase (COX), the lipoxygenase (LOX) and the cytochrome P450 monooxygenase pathways. In the COX pathway, the key step is the enzymatic conversion of arachidonic acid to the intermediate prostaglandin G2 (PGG2), which is then reduced to PGH2 by the peroxidase activity of COX. PGH2 is sequentially metabolized to prostanoids, including prostaglandins (PGs) and thromboxanes (TXs) by specific prostaglandin and thromboxane synthases. Each of the prostaglandins exerts its biological effects by binding to its cognate G protein-coupled receptor.

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be an inactive protein, which results from the alternative splicing of COX-1 [10]. Overexpression of COX-2 in tumors is usually linked to overproduction of the pro-inflammatory prostaglandin PGE2 [11,12]. Furthermore, cancer-causing agents have been reported to induce constitutive COX-2 expression, including tobacco smoke (reviewed in Ref. [13]), UV irradiation [14], essential polyunsaturated fatty acids [15–20], mitogens [21], growth factors [22–26], pro-inflammatory cytokines [24,27] and microbial agents [28–36]. Due to its pro-inflammatory potential, COX-2 overexpression may trigger the acquisition of essential cancer-cell traits [37], including evasion of apoptosis [38–43], immunosuppresion [44], sustained proliferation [45–48], angiogenesis [49–52], invasion and metastasis [53–57]. The important participation of cyclooxygenases in cancer promotion and progression is also well illustrated by models of murine carcinogenesis, as the Min mouse carrying a mutation in the APC gene [58,59] and the azoxymethane (AOM) induced tumors [60]. Several epidemiological studies have shown that the regular intake of NSAIDs, such as aspirin, ibuprofen and sulindac, inhibitors of COX, reduces the risk of cancer (for detailed reviews see references [61–63]). In colorectal cancer, sulindac, not only was shown to present chemopreventive functions in sporadic tumors, but in familial adenomatous polyposis as well [64]. Nevertheless, NSAIDs-based cancer therapies have been associated with increased risk of gastrointestinal complications, mainly due to the inhibition of COX-1 [65], and long-term administration of selective COX-2 inhibitors (coxibs) shows a strong association with higher risk of cardiovascular outcomes (myocardial infarction or stroke) [66], making the targeting of COX-2 a less attractive therapeutic strategy to pursuit. Even though this is still a main topic of discussion, important considerations must be taken before enrolling new clinical trials, including the particular genetic backgrounds that might confer additional susceptibilities to the inhibition of COX by NSAIDs [67,68] and the NSAIDs COX-independent actions [69,70]. 1.2. Epigenetics and cancer Chromatin is a dynamic structure able to change the accessibility of regulatory regions of the genome to the transcriptional machinery. In a simplified scenario, chromatin can switch between two interconvertible states manifested at structural and functional level: (1) active regions, which are transcribed or ready to start transcription upon proper stimulation and present a relaxed structure; and (2) inactive regions, which hold a repressed transcriptional state and display a condensed structure. Several epigenetic mechanisms account for the establishment of either one state or the other, including DNA methylation, modification of histones and non coding RNAs [71–75]. In humans and other mammals, DNA methylation occurs predominantly in CpG dinucleotides and is associated with transcriptional repression [76]. CpGs are not randomly distributed in the genome, but found enriched in clusters called CpG islands [76]. It is estimated that about 76% of the human genes possess a CpG island associated with their promoter regions [77] and most of them are unmethylated [76]. On the other hand, most methylated CpG sites are located in repeat elements and other inactive regions. The repressive state involves many components and layers of complexity. In brief, methylated DNA is able to recruit methyl-binding domain proteins (MBDs), together with histone deacetylases (HDACs) and other repressor elements, to promote chromatin remodeling to a compact conformation, leading to transcription impairment and acquisition of a permanent repressed state [78,79]. The epigenomic landscape varies markedly across tissue types and between individuals [75,80,81]. Recent genome-scale studies

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have revealed that most CpG methylation changes associated with development and cancer do not occur in CpG islands, but rather in sequences up to 2 kb distant, which have been termed CpG island shores [82,83]. During carcinogenesis, the epigenetic landscape is severely distorted, presenting global changes in the DNA methylation content among other epigenetic aberrations (reviewed in [75,84–87]). As a consequence, the alteration of the DNA methylation patterns may have profound consequences in human disease. Global loss of DNA methylation (hypomethylation) throughout the genome is a common feature of cancer cells and relates with the acquisition of genomic instability and activation of normally repressed genes, such as germline-specific genes. Furthermore, cancer cells also present punctual gain of DNA methylation (hypermethylation) in particular CpG islands, which results in the gene silencing of the associated genes, many of which are bona fide tumor-suppressor genes (reviewed in [84–86]) (Fig. 2). Histone tail post-translational modifications are also important regulatory epigenetic marks for transcriptional activation or repression (for review see references [74,88,89]). Histone methylation may actually be associated with both chromatin states, being the methylation of H3K4 and H3K36 generally associated with active genes, whereas the methylation of H3K9 predominantly occurs in repressed regions. As in the case of histone lysine acetylation, by weakening the histone–DNA interactions, this modification maintains chromatin in a low condensation state, being therefore found in transcribed genes. In accordance, HDACs, which reverse histone lysine acetylation, are usually considered elements of transcriptional repression [74,89]. In embryonic stem cells it has been reported the coexistence of active and inactive chromatin histone marks in a subset of genes with key functions in development and cell identity [90,91]. Noteworthy, these bivalent chromatin domains are also characteristic of the genes that become silenced in cancer by hypermethylation of the corresponding CpG island [92–94]. 2. Epigenetic alterations of the COX pathway in cancer The aberrant expression of several COX pathway genes has been recurrently shown as a frequent event in numerous malignant diseases, including colorectal, breast and lung cancer and has been related with functional features of cancer cells (reviewed in reference [3]). Current knowledge of the regulatory mechanisms involved in this deregulation mainly arises from fractioned studies generally focusing on a single gene or a short subset of genes. Few studies have pursuit an integrative perspective of the mechanisms underlying the deregulation of the COX pathway during carcinogenesis. Although, somatic mutations are not frequent, epigenetic alterations in the COX pathway, in particular DNA methylation, are recurrent events in several types of cancer (Table 1 and Fig. 3). Cumulated evidences underscore the participation of epigenetic mechanisms in the deregulation of cyclooxygenases in cancer, as well as the downstream biosynthesis and signaling of the main prostaglandins and thromboxanes and will be reviewed here. 2.1. The cyclooxygenases As mentioned above, COX is responsible for the conversion of arachidonic acid to a metabolic intermediate, PGH2, which constitutes the commitment step for prostanoid biosynthesis. The overexpression of COX-2 in tumors is a common feature of numerous cancer cells, but not a universal condition of all tumors. Even if the association between COX-2 expression and a certain type of cancer is very strong, as in colorectal and gastric cancer, a small subset of patients present unaltered levels or downregulation of COX-2. Pioneer studies from the laboratories of Issa and

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Fig. 2. Diagram of the epigenetic profile of a genomic region including a gene and a repeat element. The gene is active in normal cells and exhibits an open chromatin conformation that allows the transcription. The open chromatin conformation is characterized by low nucleosome density, presence of histone modifications associated with activity (i.e.: histone 3 lysine 4 trimethylation) and unmethylated CpG island. Alternatively the repeat element is embedded in closed chromatin. Closed chromatin is characterized by a high compactation and nucleosome density, presence of repressing histone modifications (i.e.: histone 3 lysine 9 trimethylation) and methylation of CpG dinucleotides. In tumor cells, the chromatin conformation (compactation, presence of repressing histone modifications and DNA methylation) of the promoter region of the tumor suppressor gene denotes its silencing, while the remodeled chromatin in the repeat element is associated with reactivation.

Bang revealed that the observed COX-2 downregulation in tumors of a subset of colorectal and gastric cancer patients, respectively, was strongly correlated with CpG island DNA methylation [95,96]. Furthermore, it seems that there is a strong correlation between CpG island methylator phenotype and the gain of methylation in this region in colorectal malignant growths [97]. However, recent studies have reported inconsistent profiles between COX-2 expression and the methylation status of its promoter in colorectal cancer [98], which indicates that other factors may also contribute to the downregulation of this gene in a subset of patients. In gastric cancer, it has been shown that COX-2 downregulation is also mediated by histone deacetylation [99]. Recent analyses report COX-2 CpG island hypermethylation in subsets of patients of several other cancer types, including breast [100,101], hepatic [102–104], nasopharyngeal cancer [105], prostate [106] [107], esophageal [108,109], pancreatic [110] and cervical [111–113]. Cyclooxygenase-1 (COX-1) has only been found epigenetically silenced by promoter hypermethylation in pancreatic tumors [110]. Conversely, it has also been observed that epigenetic mechanisms also contribute to COX-2 overexpression in cancer, such as chronic myelogenous leukemia (CML), which is associated with HDAC activity via CREB transcription factor [114]. Whereas in the colorectal cancer cell line HT-29 treatment with HDAC inhibitors downregulates COX-2 expression involving suppression of RNA polymerase II elongation [115]. Overexpression of COX-2 in some types of breast cancer has been associated with copy number gains [116]. Helicobacter pylori gastritis, which is intimately related to higher gastric cancer risk, has been associated with COX-2 overexpression [96,117]. Moreover, COX-2 deficient gastric epithelial cell lines, which present COX-2 hypermethylation, are less prone to augment COX-2 levels in response to H. pylori than unmethylated cell lines [118]. Following H. pylori infection, several epigenetic alterations contribute to COX-2 reactivation, such as DNA hypomethylation, release of HDACs from COX-2 promoter, increase of H3 acetylation, H3K4 dimethylation, decrease of H3K9 dimethylation and increase of H3K27 trimethylation [119]. In this case, loss of

CpG island methylation might facilitate pathogen-associated inflammation and, as a consequence, increase the risk of gastric cancer. In a pilot study that involved 40 primary gastric cancer tissues, COX-2 methylation associated with longer recurrence times and better overall survival [120]. Regarding cervical cancer is has been observed that the human papillomavirus HPV16 oncoproteins E6 and E7 are able to activate COX-2 transcription by mechanisms that include the dissociation of nuclear receptor corepressor from its promoter [111]. Finally, the presence of COX-2 mRNA in serum and feces DNA has been evaluated as marker for lung [121] and colorectal cancer respectively [122,123] and low levels of COX-2 protein are associated with better response to chemotherapy in rectal adenocarcinoma [124]. As a whole, these data support the notion that targeting the epigenetic control of COX-2 in diagnostic and therapeutic settings may have important clinical applications. 2.2. Prostaglandin E2 biosynthesis and signaling During tumorigenesis, the upregulation of COX-2 leads to a drastic increase in the levels of prostaglandin E2 (PGE2), a bioactive lipid with pleiotropic effects, most of which are related with inflammation (reviewed in reference [2]) and the acquisition of the different hallmarks of cancer [125]. Elevated levels of PGE2 can be found in colorectal, lung, breast, head and neck, and esophageal cancer, frequently correlating with poor prognosis [3,126– 129]. In addition, it has been observed that the administration of PGE2 to AOM mice induces colorectal carcinogenesis [130] and several other studies in murine models have demonstrated the close link between COX-2 derived PGE2 and tumorigenesis in colon. In Min mice, treatments with PGE2 receptor agonists were sufficient to impair NSAIDs-induced tumor regression [131]. There are three known enzymes with PGE2 synthase activity, two microsomal membrane-bound PGE2 synthases (PTGES and PTGES2, also known as mPGES-1 and mPGES-2) and a cytosolic isoform (PTGES3, also known as cPGES). Microsomal PGE2 synthase-1 is the primary responsible for inflammatory responses, being kept at low levels in most tissues, but recurrently upregulated in a number of

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I. Cebola, M.A. Peinado / Progress in Lipid Research 51 (2012) 301–313 Table 1 Genetic and epigenetic modifiers of the COX pathway regulation in Cancer. Lipid

Gene

Cancer type

Polymorphismsa

PGH2

COX-1 (PTGS1)

Colorectal

L15-L16del [222]; G213G [223]; C639A [224]

Epigenetic alterations

Pancreatic COX-2 (PTGS2)

Bile duct

837T > C [225]

Breast

169C > G [226]; rs5277 [227]; rs7550380 [228]; 8473T>C [229] 837T>C [230]

Bladder CML Colorectal Gallbladder Esophagus Gastric

Glioma Hepatic Lung Nasopharyngeal Non-melanoma skin Ovarian Pancreatic Prostate PGE2

PGI2

PGD2

PTGES EP2 (PTGER2)

EP3 (PTGER3) EP4 (PTGER4) HPGD

Hepatic Gastric Lung Neuroblastoma Colorectal Gastric Colorectal

PTGIS

Breast

PTGDS PTGDR

a b

Hypermethylation of TSS region (not a CpG island) [110]

Hypermethylation [100,101]

Induction by HDACs [114] Hypermethylation [95,123,233,234]

V102 V [231]; rs4648298 [232] 765G>C [235]; 1195G>A [236]

Hypermethylation [108] Hypermethylation [96,99,238] [120,239,240]; Hypomethylation associated with H. pylori infection [118,119]; histone deacetylation [99]; hypomethylation [241]

5939C [237]

rs20417 [242] Hypermethylation [102] 8473 C > C [243] 765 G > C [244] 765G > C and -1195A>G [245] rs5275 [246]

Hypermethylation [105] Hypermethylation [247] Hypermethylation [110] Hypermethylation [106] Hypermethylation Hypermethylation Hypermethylation Hypermethylation Hypermethylation Hypermethylation

[146]b [180] [152,153,248] [151] [155] [180]

rs2612656 and rs8752 [249] rs5602 and rs8183919 [175]; repeat polymorphism [174]

Colorectal Lung

Hypermethylation [177] Hypermethylation [178,179]; Histone deacetylation [179]b

Glioblastoma multiforme Neuroblastoma Osteosarcoma

Hypermethylation [193]

TXA2

TBXAS1 TBXA2R

Breast Colorectal

PGF2a

PTGFR

Breast Colorectal Prostate

Hypermethylation [151] Hypermethylation [201] rs41727 [175] Hypermethylation [208] Hypermethylation [219] Hypermethylation [219]

All the polymorphisms listed are associated with higher cancer risk. Analyzed in cancer cell lines only.

cancers, including colon, lung, stomach, pancreas, cervix, prostate, papillary thyroid carcinoma, head and neck, and brain [132–143]. The tumorigenic role of PTGES is further demonstrated in Min and AOM mice, where deletion of this PGE2 synthase results in the inhibition of tumorigenic development [144,145]. An induction of PTGES expression was found in a hepatocellular carcinoma cell line upon DNMT1 knockdown [146]. This observation could indicate that PTGES role in carcinogenesis is not universal, being its expression less required for hepatic cancer progression. Nevertheless, this result might be also due to a cross-reaction of other signaling pathways, not being a direct effect of PTGES demethylation. There are four PGE2 receptors, EP1, EP2, EP3 and EP4 (also known as PTGER1, PTGER2, PTGER3 and PTGER4, respectively), which mediate a variety of biological functions in several cell types. Among these, EP2 and EP4 have been mostly related with inflammatory and tumorigenic processes. In fact, EP2 is found overexpressed in esophageal, lung and colorectal cancer [128,147,148] and implicated in mouse skin papilloma and in Kaposi’s Sarcoma development [149,150]. However, it is recurrently silenced through promoter

hypermethylation in neuroblastomas and lung cancers [151–153], which suggests that it is not required for tumor progression in these tissues. In addition, it was recently shown in vitro that EP4 is involved in angiogenesis through activation of protein kinase A (PKA) [154]. The EP3 receptor may also undergo epigenetic silencing during carcinogenesis by promoter hypermethylation in mouse, rat and human colorectal tumors [155]. In contrast with COX-2, the responsible for the cytosolic degradation of PGE2, 15-hydroxyprostaglandin dehydrogenase (HPGD), is highly expressed in non-neoplastic tissues and often downregulated in colon, gastric, lung and breast cancer, which contributes for the accumulation of PGE2 in cancer cells [156– 161]. In colorectal cancer, HPGD silencing is mediated by HDACs and, in tumors from patients, elevated HDAC expression correlates with HPGD downregulation [162]. This mechanism of gene silencing seems to be common to colorectal and lung cancer, since the treatment of lung adenocarcinoma cells with HDAC inhibitors induces chromatin remodeling and HPGD re-expression [163].

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Fig. 3. Effectors of the Cox pathway (either synthases or receptors) silenced by promoter DNA hypermethylation in different tumor types. Hypermethylated genes are shown in red boxes and linked to the cancer types in which have been reported to be epigenetically repressed.

In addition to the epigenetic mechanisms mentioned above, there is a growing body of evidence showing that microRNAs are important in the regulation of inflammatory processes and in particular for prostaglandin synthesis, especially at the level of PGE2 synthesis and signaling (reviewed in reference [164]).

2.3. Prostacyclin biosynthesis and signaling Prostacyclin (also referred as prostaglandin I2 or PGI2) is a potent vasodilator and platelet aggregation inhibitor. Mostly studied as putative target for the treatment of cardiovascular system malfunctions [165,166], its role in carcinogenesis remains uncertain. Hypoxia appears to increase the overexpression of prostacyclin synthase (PTGIS, also known as PGIS) in vascular cells, which results in high levels of prostacyclin in highly vascularized tissues [167]. It has been suggested that this mechanism may counteract the negative effects of inflammatory stimuli [167]. Overexpression PTGIS induces apoptosis through nuclear receptor PPARd-specific signaling in HEK 293T cells [168], and it has been shown to be anti-tumorigenic in lung cancer models [169–172]. Furthermore, iloprost, a prostacyclin analog, induces apoptosis in vascular smooth muscle [173]. It was also reported that polymorphisms at PTGIS promoter conferring lower expression levels are significantly associated with higher risk of colorectal cancer and lower chemopreventive action of NSAIDs [174]. In addition, Abraham et al. observed differential susceptibility and survival rates of breast cancer patients with different variants of PTGIS [175]. However, prostacyclin appears to have a complex mechanism of action, which is most likely context-dependent as Cutler et al. observed that the stromal production of prostacyclin in the colon is able to protect epithelial cells from entering apoptosis [176]. Very few studies have addressed the epigenetic mechanisms that modulate PTGIS expression in cancer. We have shown that PTGIS suffers an epigenetic deregulation in colorectal cancer by promoter hypermethylation, which is significantly associated with transcriptional silencing and aneuploidy in several cancer cell lines and human tumors [177]. Subsequent works from Stearman et al.

and Cathcart et al. showed that PTGIS also undergoes epigenetic silencing in lung cancer cell lines and tissues [178,179]. Although at the moment there are no specific reports on the epigenetic regulation of the prostacyclin concomitant surface receptor IP (also known as PTGIR), its mRNA, along with that of two prostaglandin E2 receptors, EP2 and EP4, was found upregulated in a metastatic gastric cancer cell line upon treatment with the DNA-methyl-transferase inhibitor 5-aza-2-deoxycytidine in a cDNA microarray analysis [180]. However, it is not clear whether these genes are directly regulated by epigenetic mechanisms, or if the observed upregulation is only an indirect effect of alterations in the expression of other genes. Further studies should address the potential epigenetic silencing of these genes and their functional implications in tumorigenesis. In addition to the cell-surface receptor, prostacyclin is able to bind to different members of the PPAR nuclear receptor family. Prostacyclin was reported to signal through PPARd [181] and PPARc, being able to induce apoptosis [168] or growth arrest [182] in particular cellular contexts. Yang et al. have reported that RNA interference against PPARd promoted colorectal cancer cell proliferation [183]. However, the role of PPARd in cancer, especially in colorectal and breast cancers, is controversial, and some reports show that PPARd activation may promote cell proliferation and tumor progression [184,185]. At the moment, we have no knowledge of reports on epigenetic mechanisms regulating PPARd expression. As in the case of PPARc, its expression in colorectal tumors correlates with good prognosis [186], but it may also undergo epigenetic silencing through promoter hypermethylation, being this event associated with poor prognosis [187]. 2.4. Prostaglandin D2 biosynthesis and signaling Similarly to prostacyclin, prostaglandin D2 (PGD2) is a vasodilator and inhibits platelet aggregation. Preferentially produced in the brain, it plays an important role in the central nervous system modulation, being important for the regulation of sleep, as well as allergic and pain responses, through PGD2 receptor-mediated signaling [188,189]. Noteworthy, this eicosanoid may suffer

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further dehydration to produce PGJ2, D12-PGJ2, and 15-deoxyD(12,14)-PGJ2, being the last a natural ligand for the nuclear receptor PPARc (mentioned in the previous section). Two distinct forms of PGD2 synthase have been described: the lipocalin-type (PTGDS, also known as L-PGDS) and the hematopoietic (HPGDS, also known as H-PGDS). The first is mostly found in the central nervous system, male genital organs and heart, where it functions as a lipophilic ligand-binding protein as well. On the other hand, the hematopoietic form, HPGDS, can be found ubiquitously expressed in peripheral tissues, being preferentially expressed in antigen-presenting cells, mast cells, and megakaryocytes [189]. High levels of PTGDS were found in breast, brain and ovarian cancers [190–192]. In contrast, it was recently reported that PTGDS is recurrently downregulated in astrocytomas, by aberrant hypermethylation of the first introns [193], and in lung tumors, although in this case the silencing mechanisms have not been described yet [194]. Prostaglandin D2, may bind and signal through two G proteincoupled receptors, PTGDR (also known as DP1) and CRTH2 (Chemoattractant Receptor-Homologous expressed on T Helper type 2 cells, also referred as DP2). Activation of PTGDR is involved in the regulation of several physiological and pathological processes, such as sleep, allergic responses [195] and, importantly, cell survival and angiogenesis [196,197], whereas CRTH2 is thought to be mainly involved in the induction of chemotaxis in T helper type 2 cells, eosinophils, and basophils [198]. Apparently, only PTGDR is subjected to gene expression modulationin colorectalcancer,being significantly downregulatedin tumors [199]. Interestingly, when characterizing the PGD2 receptors expression in a panel of colorectal cancer cell lines, Hawcroft et al. could only detect expression of PTGDR in one cell line [200]. Although the mechanisms responsible of the downregulation or silencing of this gene in colorectal cancer have not been studied yet, its promoter was already found hypermethylated in osteosarcoma and neuroblastoma cell lines [151,201], being this mechanism likely to mediate PTGDR silencing in colorectal carcinogenesis as well.

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pressure, renal filtration, induction of luteolysis, inhibition of adipocyte differentiation and hair growth stimulation [209]. In addition, PGF2a has been shown to promote carcinogen-induced malignant transformation in C3H/M2 mouse fibroblasts [210]. Moreover, colorectal cancer cells produce high levels of this prostanoid, which, in this context, is able to stimulate cell motility and invasion [211]. The biosynthesis of PGF2a may occur via three distinct pathways: from PGE2, PGD2 or PGH2, by PGE 9-ketoreductase (AKR1C5), PGD 11-ketoreductase (AKR1C3) or PGH 9-, 11-endoperoxide reductase (AKR1C3), respectively. Despite the abundance of PGF2a synthases, most of them belong to the aldo–keto reductase superfamily [209,212,213]. Of particular interest from the therapeutic point of view is AKR1B1 (aldo–keto reductase family 1 member B1), which is the major responsible for human endometrium PGF2a production [214] and may be implicated in hepatic tumorigenesis [215]. Conversely, its silencing has been reported in sporadic adrenocortical and colorectal tumors [216,217]. In a comparative study of colorectal cancer samples, AKR1B10, another member of the AKR1B family, with weaker PGF2a synthase activity [209], was found downregulated in 88% of the analyzed tumors [217]. So far, we have no knowledge of studies regarding the epigenetic regulation of the PGF2a synthases. Similarly to other prostanoids, PGF2a binds to a cognate G protein-coupled receptor (PTGFR, also known as FP). The PTGFR-mediated signaling has been related with enhanced epithelial cell proliferation in endometrial adenocarcinoma [218]. However, in a genome-wide analysis of cancer cell methylation, the PTGFR promoter was found epigenetically silenced by promoter methylation in a prostate cancer cell line and in colorectal tumors [219]. Loss of heterozygosity affecting this gene is frequent in human breast tumors, supporting its possible involvement in cancer [220]. Importantly, PGF2a is also able to bind to the PGE2 receptors EP1 and EP3 with high affinity [221], adding further complexity into the understanding of the biological role of PGF2a.

2.5. Thromboxane A2 biosynthesis and signaling In opposition to prostacyclin, thromboxane A2 (TXA2) is a powerful vasoconstrictor and platelet aggregation mediator. Thromboxane synthase (TBXAS1, also known as TXAS) overexpression has been observed in a number of cancer types, including papillary thyroid carcinoma [202], bladder [203], prostate [204] and colorectal [205], and its expression is generally negatively associated with survival. When comparing different human cell lines, Lee et al. found cell-specific signatures in the methylation pattern of the TBXAS1 promoter. Surprisingly, higher expression levels could only be observed in the cell lines that presented hypermethylation of this promoter [206]. The thromboxane receptor (TP, also known as TBXA2R) has been found commonly expressed in breast cancer tumors [207]. On the other hand, in a molecular screening designed to detect alterations in the patterns of methylation, Paz et al. identified the thromboxane receptor as a putative target of promoter hypermethylation and transcriptional silencing in colorectal cancer. In the same study, re-introduction of this receptor in the colorectal cancer cell line HCT116 resulted in colony formation inhibition [208]. According to these results, the role of TXA2 varies amongst different cancer types and epigenetic mechanisms may be involved in the regulation of both synthesis and membrane–receptor-mediated activity. 2.6. Prostaglandin F2a biosynthesis and signaling Prostaglandin F2a (PGF2a) is involved in biological processes as diverse as smooth muscle contraction, regulation of intraocular

3. Concluding remarks The COX pathway is involved in the regulation of multiple cellular functions that are critical in the tumorigenic process (Fig. 1). This implies that its study represents a prime target in all the strategies against cancer, from prevention and risk assessment to diagnosis, prognosis and treatment. With the advent of epigenetic analyses in the last decade, it has been uncovered that promoter DNA methylation, histone deacetylation and microRNA differential expression, among other modifications, participate in the abnormal expression of several members of the COX pathway during carcinogenesis (summarized in Table 1 and Fig. 3). Despite the abundant literature pointing up the deregulation of one or more of these genes in a particular type of cancer, there is a lack of studies targeting the analysis of this complex pathway as a functional unit. Comprehensive epigenetic profiling of the elements of the COX pathway is needed to delineate an integrated chart of the pathway regulation and the cellular mechanisms modulated by the different prostaglandins and their ligands in physiological but especially in pathological situations, as inflammation and cancer. Gene silencing by DNA hypermethylation of the promoter-associated CpG island of different genes of the COX pathway is the most frequently reported alteration in particular types of cancer. This is probably due to technical constrictions, since, so far, DNA methylation is the most accessible epigenetic mark to be tested in tissue samples. Technical advances are needed to analyze other epigenetic modifications in a consistent way.

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Fig. 4. Deregulation of the COX pathway in cancer. It is known that lifestyle factors, such as high-fat diets and tobacco smoking, particular genetic backgrounds, and epigenetic alterations may contribute to the deregulation of the COX pathway in chronic inflammation pathologies and cancer. Most often, this deregulation results in a generalized overproduction and downstream cognate receptor-mediated activity of prostaglandin E2 over the other possible products of this metabolic pathway (other PG, other prostaglandins).

The epigenetic deregulation of some of effectors of the COX pathway in inflammation and cancer collapses the balance between prostaglandins and results in loss of compensating mechanisms (Fig. 4), which results in functional impairments. Epigenetics acts as a bidirectional control of the COX pathway that gauges and modulates the impact of exogenous and endogenous factors at multiple levels. Hence, the understanding of the contribution of environmental factors and the genetic background to inflammation and cancer cannot be achieved without a deep understanding of the epigenetic mechanisms involved in the fine regulation and integration of environmental and molecular information. The development and application of personalized and more effective therapies in cancer is based in a better knowledge of the molecular mechanisms underlying disease and normal physiology. Future studies should tackle the complete profiling of the COX pathway at functional level, and this includes the epigenetic mechanisms controlling its different components. Acknowledgements I.C. was supported by a fellowship from the Fundação para a Ciência e a Tecnologia. Research in the lab was supported by grants from the Spanish Ministry of Science and Innovation (SAF2008/ 1409, SAF2011/23638, CSD2006/49) and Generalitat de Catalunya (2009 SGR 1356). References [1] Woutersen RA, Appel MJ, van Garderen-Hoetmer A, Wijnands MV. Dietary fat and carcinogenesis. Mutat Res 1999;443:111–27. [2] Greene ER, Huang S, Serhan CN, Panigrahy D. Regulation of inflammation in cancer by eicosanoids. Prostaglandins Other Lipid Mediators 2011;96:27–36. [3] Wang D, Dubois RN. Eicosanoids and cancer. Nat Rev Cancer 2010;10:181–93. [4] Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, Dubois RN. Upregulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994;107:1183–8. [5] Ristimäki A, Honkanen N, Jänkälä H, Sipponen P, Härkönen M. Expression of cyclooxygenase-2 in human gastric carcinoma. Cancer Res 1997;57:1276–80. [6] Wolff H, Saukkonen K, Anttila S, Karjalainen A, Vainio H, Ristimäki A. Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res 1998;58:4997–5001. [7] Liu XH, Rose DP. Differential expression and regulation of cyclooxygenase-1 and -2 in two human breast cancer cell lines. Cancer Res 1996;56:5125–7. [8] Zidar N, Odar K, Glavac D, Jerse M, Zupanc T, Stajer D. Cyclooxygenase in normal human tissues: is COX-1 really a constitutive isoform, and COX-2 an inducible isoform? J Cell Mol Med 2009;13:3753–63. [9] Bauer AK, Dwyer-Nield LD, Malkinson AM. High cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2) contents in mouse lung tumors. Carcinogenesis 2000;21:543–50. [10] Nurmi JT, Puolakkainen PA, Rautonen NE. Intron 1 retaining cyclooxygenase 1 splice variant is induced by osmotic stress in human intestinal epithelial cells. Prostaglandins Leukotrienes Essent Fatty Acids 2005;73:343–50. [11] Chell S, Kaidi A, Williams AC, Paraskeva C. Mediators of PGE2 synthesis and signalling downstream of COX-2 represent potential targets for the

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