Abstract
ANIMAL CELLS AND SYSTEMS 2023, VOL. 27, NO. 1, 61–71 https://doi.org/10.1080/19768354.2023.2189933 Emerging roles of polyunsaturated fatty acid synthesis pathway in colorectal cancer Young-Ah Moon Department of Molecular Medicine, Inha University College of Medicine, Incheon, South Korea ABSTRACT ARTICLE HISTORY Received 11 November 2022 The development of colorectal cancer typically involves the accumulated influences of genetic Revised 14 February 2023 alterations, medical issues, lifestyle, and diet. Dietary fatty acids appear to affect the Accepted 3 March 2023 tumorigenesis and progression of colorectal cancer. Despite conflicting results, the current consensus on the effects of very long-chain polyunsaturated fatty acids on colorectal cancer is KEYWORDS that low levels of eicosapentaenoic acid and docosahexaenoic acid, and high levels of colorectal cancer; arachidonic acid are associated with an increased risk of colorectal cancer. Altered levels of polyunsaturated fatty acid; arachidonic acid in membrane phospholipids can change the levels of prostaglandin E , which 2 ELOVL5; FADS2; arachidonic affect the biological activities of cancer cells in multiple stages. Arachidonic acid and other very acid long-chain polyunsaturated fatty acids can affect tumorigenesis in prostaglandin E - independent manners as well, including stabilization of β-catenine, ferroptosis, ROS generation, regulation of transcription factors, and de novo lipogenesis. Recent studies have revealed an association between the activities of enzymes synthesizing very long-chain polyunsaturated fatty acids and tumorigenesis and cancer progression, although the mechanisms are still unknown. In this study, PUFA effects on tumorigenesis, the endogenous very long-chain polyunsaturated fatty acid synthesis pathway, metabolites of arachidonic acid and their effects on tumorigenesis and progression of CRC, and current knowledge that supports the association of the enzymes involved in the polyunsaturated fatty acid synthesis pathway with colorectal cancer tumorigenesis and progression are reviewed. Introduction genome analysis and transcriptomic studies using CRC tissues and cell lines have revealed alterations in gene Colorectal cancer (CRC) is the third most common cancer expression related to VL-PUFA synthesis and metabolism and second most common cause of cancer-related death during tumorigenesis and progression of CRC, implicat- globally (WHO 2022). Accumulation of various factors ing these genes as therapeutic targets for cancer treat- accounts for most cases of CRC. These factors include ment, as well as markers to assess the severity of genetic alterations; medical issues, such as a family cancer or prognosis. history of CRC, inflammatory bowel disease, obesity, This review overviews PUFA effects on tumorigenesis, and diabetes. Smoking, excessive alcohol consumption, the endogenous VL-PUFA synthesis pathway and physical activity, and dietary factors that include meat, enzymes, metabolites of arachidonic acid and their vegetables, dietary fiber, and fish consumption are also effects on tumorigenesis and progression of CRC, critical factors in the development of CRC (Thanikacha- expression changes of genes involved in VL-PUFA syn- lam and Khan 2019; Li et al. 2021). thesis and metabolism, and epigenetic regulation of Dietary fats, especially dietary fatty acids, appear to elongase of very long fatty acid 5 (ELOVL5) in cancer. affect he tumorigenesis and progression of CRC. Epide- miological studies have suggested that saturated fatty acids and ω-6 very long chain (VL)-polyunsaturated Effects of PUFAs on tumorigenesis fatty acids (PUFAs) may enhance colorectal carcinogen- esis, whereas ω-3 VL-PUFAs may have protective Linoleic (C18:2, ω-6), α-linolenic acid (C18:3, ω-3), arachi- effects (Van Blarigan et al. 2018), although more donic acid (C20:4, ω-6), eicosapentaenoic acid (EPA, studies are still needed to establish their effects and C20:5, ω-3), and docosahexaenoic acid (DHA, C22:6, the mechanisms involved. Over the last decade, whole ω-3) are the major components of membrane CONTACT Young-Ah Moon yamoon15@inha.ac.kr Department of Molecular Medicine, Inha University College of Medicine, Incheon, South Korea © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. 62 Y.-A. MOON phospholipids. VL-PUFAs with more than 20 carbons Hall et al. 2008; Calder 2017; Burns et al. 2018; Innes and (C20) also have various biological activities. They are Calder 2018; Bae et al. 2020; Dierge et al. 2021). ligands for nuclear receptors, including peroxisome pro- Population-based studies designed to determine the liferator-activated receptors and liver X receptors (LXRs) association between FA intake and CRC have demon- (Chambrier et al. 2002; Yoshikawa et al. 2002; Bordoni strated conflicting results, including a lack of association et al. 2006). VL-PUFAs are also regulators of transcription (Sasazuki et al. 2011; Sakai et al. 2012; Hodge et al. 2015). factors, such as sterol regulatory element binding The influence of genetic variations in genes related to protein-1 (SREBP-1) and carbohydrate element binding prostanoid synthesis, such as prostaglandin-endoperox- protein (ChREBP) (Hannah et al. 2001; Dentin et al. ide synthase (PTGS) 1, PTGS2, arachidonate lipoxygenase 2006). Their metabolites, which include eicosanoids (ALOX) 12, ALOX5, ALOX15, and 5-lipoxygenase activat- and resolvins, act as signaling molecules in various phys- ing protein, has been proposed as a reason for the iological and pathological processes. Because of these inconsistent results of dietary VL-PUFAs on CRC risk essential roles, deficiencies in PUFAs result in disease (Habermann et al. 2013). Currently, the consensus on conditions (Spector and Kim 2015). Conversely, many VL-PUFA on CRC seems to be that low levels of EPA clinical and epidemiologic studies have revealed that and DHA, and high levels of arachidonic acid are associ- VL-PUFAs, especially in the form of ω-3, which is rich in ated with an increased risk of CRC (Pot et al. 2008). Simi- fish oil, have beneficial effects on the prevention and larly, dietary supplementation with ω-3 PUFA and ω-6 improvement of cardiovascular and metabolic diseases PUFA suppresses and enhances, respectively, the risk (Burns et al. 2018). The effects of VL-PUFAs on inflam- of CRC (Hardman 2004; Hall et al. 2008; Sasazuki et al. mation and cancer have not yet been clearly defined, 2011; May-Wilson et al. 2017). Arachidonic acid seems and various studies have reported both pro-/anti-inflam- to increase colon cancer cell growth, whereas DHA matory and pro-/anti-tumorigenic roles (Hardman 2004; acts in another way (Habbel et al. 2009). Therefore, sup- plementation of ω-3 PUFA has been used in cancer treat- ment to minimize resistance and improve the efficacy of radiotherapy and chemotherapy (Hardman 2004; Duper- tuis et al. 2007). One of the ways in which ω-6 arachido- nic acid affects colon cancer cells may be mediated by the production of prostaglandins (PGs), whereas ω-3 PUFAs inhibit PG production from ω-6 PUFA (Dupertuis et al. 2007; Habbel et al. 2009). Independent of PG pro- duction, arachidonic acid could be pro-tumorigenic by stabilizing β-catenin through direct interaction with Fas-associated factor 1 (FAF1), thus stimulating tumor growth (Kim et al. 2015). The peroxidation of PUFAs induces oxidative stress in cells, which can be pro- inflammatory and pro-carcinogenic (Cai et al. 2012). In contrast, peroxidation of PUFAs can be cytotoxic and tumor-suppressive in CRC cells (Dupertuis et al. 2007). VL-PUFAs of both ω-6 and ω-3 can mediate anti-cancer effects through ferroptosis, an iron-dependent form of programed cell death (Dixon et al. 2012) characterized by the accumulation of lipid peroxides (Dierge et al. 2021). The conditions and mechanisms of the effects of ω-6 and ω-3 PUFAs on CRC are unclear, and further studies are required. Generation of endogenous VL-PUFAs Linoleic and α-linolenic acids are essential fatty acids with 18 carbons. They cannot be synthesized in mamma- Figure 1. Fatty acid elongation system. Fatty acids longer than lian cells and must be supplied in the diet (Spector and C18 are elongated through the fatty acid elongation system on Kim 2015). Longer chain PUFAs with more double bonds the endoplasmic reticulum membrane. R represents the fatty acyl chain. than linoleic and α-linolenic acid in the ω-6 and ω-3 ANIMAL CELLS AND SYSTEMS 63 series can be generated through reactions that are per- cycle, the condensation step catalyzed by ELOVLs is formed by FA elongation and desaturation systems on the rate-limiting step. Seven ELOVLs (ELOVL1, 2, 3, 4, 5, the endoplasmic reticulum (ER) membrane in cells 6, and 7) exist in mammals (Jump 2009). Each ELOVL (Cinti et al. 1992). Arachidonic acid, EPA, and DHA are exhibits substrate specificity for fatty acyl-CoA with representative VL-PUFAs generated from linoleic and different chain lengths and numbers of double bonds, α-linolenic acid through these systems (Spector and and is expressed in a tissue-specific manner. However, Kim 2015). other enzymes that comprise the elongation system FAs longer than 18 carbons are generated by the FA seem to possess no substrate specificity and are ubiqui- elongation system on the ER membrane (Figure 1) tously expressed in all tissues (Moon and Horton 2003). (Cinti et al. 1992). This system adds two carbons to pre- To generate arachidonic acid, EPA, and DHA from existing fatty acyl-CoA through a cycle of four consecu- linoleic and α-linolenic acid, ELOVL2, ELOVL5, fatty acid tive reactions of condensation, reduction, dehydration, desaturase 1 (Δ5 desaturase; FADS1), and FADS2 (Δ6 and reduction. Each reaction is catalyzed by a separate desaturase) involve the reactions (Figure 2). Linoleic enzyme. Condensation between malonyl-CoA and pre- and α-linolenic acids are reduced to γ-linolenic acid existing fatty acyl-CoA to generate β-ketoacyl-CoA is cat- and stearidonic acid by FADS2, followed by elongation alyzed by ELOVLs. Next, β-ketoacyl reductase, also to dihomo- γ-linolenic acid (C20:3, ω-6) and ETA (C20:4, known as 17-beta hydroxysteroid dehydrogenase 12 ω-3) by ELOVL5. Following reduction by FADS1, arachi- (HSD17B12), catalyzes the generation of β-hydroxyacyl- donic acid and EPA are generated. ELOVL2 is involved CoA from β-ketoacyl-CoA using NADPH as a reducing in the elongation of PUFAs longer than C20 and C22, cofactor. Next, trans-2,3-enoly-CoA is generated by the and peroxisomal degradation may additionally occur catalytic action of dehydratase, followed by another to generate DHA (Jakobsson et al. 2006)(Figure 2). The reduction catalyzed by trans-2,3-enoly-CoA reductase importance of ELOVL5 in maintaining VL-PUFA in the (TECR) using NADPH to generate the final 2-carbon cell was demonstrated in Elovl5 knock out mice. The elongated fatty acyl-CoA (Cinti et al. 1992). In this lack of ELOVL5 resulted in a reduction in cellular VL- PUFA content, and the phospholipid class displayed the greatest change (Moon et al. 2009). Metabolites of arachidonic acid and effects on cancer Arachidonic acid is a precursor of C20 eicosanoids. Ara- chidonic acid at the sn-2 position of membrane phos- pholipids is released by phospholipase A2 and can be oxidized by the catalytic actions of cyclooxygenase (COX, also known as prostaglandin-endoperoxide synthase [PTGS]), P-450 epoxygenase, and lipoxygenase (LOX) (Patel et al. 2008). The COX pathway generates five primary prostanoids that include prostaglandin (PG) D , PGE , PGF , PGI , and thromboxane A , which are sig- 2 2α 2 2 naling molecules with short half-lives that act in a para- crine or autocrine manner (Patel et al. 2008). Prostanoids play important roles in general physiological and patho- logical processes, including inflammation, fever, smooth muscle constriction and relaxation, vascular constriction and relaxation, platelet aggregation, ovulation, and labor. The two major isoforms of COX (COX-1 and COX-2) act in the same fashion to generate prostanoids, but with different expression patterns in humans. COX-1 is constitutively expressed in most tissues, whereas COX- 2 expression is induced in certain pathological con- Figure 2. VL-PUFA synthesis pathway. Arachidonic acid, EPA, ditions. Selective inhibition of COX-2 can reduce the and DHA are the major VL-PUFAs synthesized from linoleic side effects generated by inhibiting the physiological and α-linolenic acid by fatty acid elongases and desaturases that exist on the endoplasmic reticulum membrane. processes performed by COX-1 (Patel et al. 2008). 64 Y.-A. MOON The eicosanoids produced are secreted into the extra- reduce PGE and produce anti-cancer effects (Dannen- cellular microenvironment and bind to their specific berg et al. 2001). Randomized controlled trials demon- receptors on the plasma membrane. PGD binds to pros- strated that regular use of aspirin for >20 years could taglandin D receptor (DP), PGE to prostaglandin E reduce the long-term incidence and mortality of CRC 2 2 2 receptors (Eps), PGF to prostaglandin F receptor (Rothwell et al. 2010). Regular use of nonselective 2α 2α (FP), PGI to prostacyclin receptors (IPs), and TXA to NSAIDs and selective COX-2 inhibitors over 10–15 2 2 thromboxane receptor (TBXA2R). Generally, PG path- years reduced the development of colorectal cancer by ways contribute to tumorigenesis by mediating cell pro- 40%–50%, and reduced the number and size of adeno- liferation, growth, apoptosis, invasion, migration, mas in patients with familial adenomatous polyposis metastasis, and angiogenesis. Thus, PGs are critical (Wang et al. 2005). While NSAIDs reduced the risk of mediators of cancer (Wang et al. 2015). CRC associated with COX-2 overexpression, no effect PGE is one of the major PGs produced by COX was observed in CRC with weak or absent expression protein and the most abundant PG found in CRC (Cai of COX-2 (Chan et al. 2007). Selective COX-2 inhibitors et al. 2006; Wang et al. 2015). PGE binds to its specific have been included in therapeutic strategies, either as receptors, EP1–EP4. These are G-protein-coupled recep- a prophylactic or adjuvant treatment for chemotherapy tors that transfer their signals via different signaling or radiotherapy (Hashemi Goradel et al. 2019). These pathways. G proteins coupled with EPs give rise to results suggest that PGE is important in CRC, and that 2+ second messengers that include cAMP, Ca , and inositol the level of precursor arachidonic acid might affect triphosphate (IP ) to initiate downstream signaling often PGE production. 3 2 associated with tumor growth and metastasis. The sig- naling includes the phosphoinositide 3-kinase (PI3K), Enzymes involved in VL-PUPA synthesis in mitogen-activated protein kinase (MAPK) pathway, NF- CRC κB, and β-catenin/T-cell factor signaling (Wang et al. 2022). PGE effects on cancer cell proliferation and Reprograming of cellular metabolic processes is a metastasis have been studied in cultured cells and in feature of cancer cells that leads to changes in various types of human cancers, including CRC, breast enzymes involved in de novo lipogenesis and FA cancer, lung cancer, liver cancer, gastrointestinal profiles (Peck and Schulze 2016). Cellular changes occur- cancer, pancreatic cancer, and renal and urinary cancer ring upon alteration in arachidonic acid content in mem- (Jara-Gutiérrez and Baladrón 2021). PGE affects multiple brane phospholipids have been demonstrated in stages of cancer, including carcinogenesis, tumor cell endothelial cells. In the study, arachidonic acid content proliferation, invasion, and interaction between tumor affected the viscosity of the cell membrane and thus cel- and immune cells (Wang et al. 2015). lular motion, and regulated cell adhesion and migration Chronic inflammation is an important risk factor for (Rossen et al. 2011). The increased arachidonic acid the development of CRC (Ogino et al. 2011; Cai et al. content in phosphatidylinositol at the cancer cell/ 2012). COX-2 expression is upregulated during inflam- stromal cell interface in CRC patients may imply the mation and PGE synthesis is increased, which can influence of arachidonic acid content in cancer pro- alter cytokine balance and expression of PG receptors, gression (Hiraide et al. 2016). Moreover, arachidonic as well as activate cell proliferation (Mutoh et al. 2006). acid in membrane phospholipids is a source of PGE , PGE levels and expression of COX-2 are also increased which affects multiple stages of cancer. As described in colon tumors compared with the surrounding earlier, VL-PUFAs other than arachidonic acid can also normal tissue in mouse models and human patients affect CRC. Therefore, changes in the activities of (Sano et al. 1995). In the colon, PGE has been associated enzyme components in the VL-PUFA synthesis with polyp formation and tumorigenesis (Mutoh et al. pathway could influence CRC cells in various ways, 2006). In a rat colon tumor model induced by azoxy- including PGE -dependent and -independent manners. methane, the addition of PGE for 25 weeks significantly An inclusive list of published data of the association of increased the incidence of tumors, suggesting that PGE ELOVL5, FADS2, and HSD17B12 with CRC and other is involved in tumorigenesis and that inhibition of the types of cancers are shown in Tables 1 and 2, receptors or PGE synthesis can be targets for the pre- respectively. vention and treatment of CRC (Wang et al. 2005; ELOVL5: ELOVL5 activity is essential for maintaining Mutoh et al. 2006). Experimental evidence of the invol- VL-PUFA levels in phospholipids, as shown in a study −/− vement of PGE in tumorigenesis and cancer metastasis involving Elovl5 mice (Moon et al. 2009). Therefore, has led to the use of COX inhibitors, including aspirin changes in the expression of ELOVL5 in cancer cells and nonsteroidal anti-inflammatory drugs (NSAIDs), to would change the VL-PUFA profile and affect the ANIMAL CELLS AND SYSTEMS 65 Table 1. Association of genes in VL-PUFA synthesis with human proliferation and progression of cancer cells. According colorectal cancer (CRC). to a Gene Expression Omnibus (GEO) profile (GDS4296) Summary Reference using various CRC cell lines, COLO205, HCC 2998, ELOVL5 HCT116, KM12, and SW 620 cells exhibited high Genome-wide genotyping array of 3494 (Phipps et al. 2015) expression of ELOVL5, whereas ELOVL5 expression was individuals with invasive CRC revealed SNPs at 6p12.1, where the nearest gene was ELOVL5. negligible in HCT 15 and HT 29 cells (Figure 3(A)). The strongest association was shown for ELOVL5 expression in CRC is inversely associated with rs209489 with poorer survival, especially in individuals with distant metastatic CRC. the prognosis of patients with CRC. The Cancer Increased expression of ELOVL5 was found in (Mokhtari et al. Genome Atlas (TCGA) survival data that linked ELOVL5 tumor samples in a TCGA data set (GSE20931). 2022) Transcription of ELOVL5 was downregulated (Boot et al. 2017) expression level with overall survival of patients with through DNA hypermethylation in the low colon adenocarcinoma revealed better survival rates passage CRC cell lines with BRAF mutation for patients with low expression of ELOVL5 (<10th per- isolated from cancer tissue. Colon cancer epithelial cells were isolated from (Hofmanová et al. centile) compared to patients with high expression of colon cancer patients. Expression of fatty acid 2021) ELOVL5 (>50th percentile) (Figure 3(B)). Genome analysis synthase, stearoyl-CoA desaturate, ELOVL2, and ELOVL5 were increased in the cancer cells. has demonstrated increased expression of ELOVL5 in Significant changes in ratios of fatty acids in human CRC and other types of cancers, including phospholipid classes were detected. FADS2 breast, prostate, and kidney cancers. The findings Increased expression of FADS2 was found in (Mokhtari et al. suggest the involvement of ELOVL5 in cancer cell pro- tumor samples in a TCGA data set (GSE20931). 2022) HSD17B12 liferation and invasion, although its effects and mechan- Increased expression of HSD17B12 was found in (Mokhtari et al. isms remain unclear. Study data on the association tumor samples in a TCGA data set (GSE20931). 2022) between ELOVL5 expression and cancers are presented Increased risk of death and progression of (Lin et al. 2020) colorectal cancer in patients with 10838164 C>T in Tables 1 and 2. genetic variant was reported, which was Gene expression analysis of CRC using GEO dataset correlated with increased transcriptional activity and upregulation of HSD17B12. GSE20931 showed that the expression of ELOVL5, FADS2, HSD17B12, and trans-2,3-enoyl-CoA reductase (TECR), the enzymes involved in PUFA elongation and Table 2. Association of genes in VL-PUFA synthesis with human cancers other than CRC. Cancer type Summary Reference ELOVL5 Gastric cancer ELOVL5 expression was upregulated and led to ferroptosis sensitization in mesenchymal type gastric cancer cells (Lee et al. 2020) Breast cancer Expression levels of ELOVL1, 5, and 6 were significantly upregulated in triple-negative tumors. (Yamashita et al. 2017) Decreased expression of ELOVL5 and IGFBP6 was associated with poor prognosis. (Shkurnikov et al. 2019) Knockdown of ELOVL5 and IGFBP6 genes increased the expression of matrix metalloproteinase 1 and decreased (Nikulin et al. 2021) intercellular adhesion, suggesting more efficient invasion of tumor cells. Reduced expression of ELOVL5 and IGFBP6 genes in tumor cells could lead metastasis with a higher probability. Prostate cancer High expression of ELOVL5 was suggested as a potential marker of prostate cancer and higher incidence of (Romanuik et al. 2009) metastasis. Potent and direct androgen receptor-mediated induction of ELOVL5 was presented in prostate cancer cell. (Centenera et al. 2021) Patient-derived cells revealed that ELOVL5 expression was upregulated in prostate cancer compared with nonmalignant prostate. Renal cell High level of ELOVL5 correlated with higher clinical staging and poor clinical prognosis. High expression of (Nitta et al. 2022) carcinoma ELOVL5 was negatively associated with overall survival in a TCGA database. Knockout of ELOVL5 in the cancer cells suppressed proliferation and induced apoptosis in ACHN and 786-O (Nitta et al. 2022) cancer cells. The knockout inhibited in vivo tumor growth. FADS2 Breast cancer FADS2 activity was increased in cancerous tissue. Cancerous tissue contained higher levels of C20:3, ω-6 and (Pender-Cudlip et al. arachidonic acid than adjacent noncancerous tissue did. It was associated with PGE level especially in estrogen 2013) receptor-negative cancer. HSD17B12 Breast cancer Immunoreactivity of HSD17B12 was significantly associated with poor prognosis of patients. (Nagasaki et al. 2009) RNA interference of HSD17B12 resulted in COX-2 dependent growth inhibition in SK-BR-3 cancer cells. Cell (Nagasaki et al. 2009) growth was recovered by addition of arachidonic acid. Knockdown of HSD17B12 increased proliferation and migration of MCF7 and MDA-MB-453 cells. (Tsachaki et al. 2020) Knockdown of HSD17B12 decreased proliferation of SUM159 cells. (Tsachaki et al. 2020) Ovarian cancer HSD17B12 expression in cancer tissue was suggested as a marker of poor prognosis. Silencing of HSD17B12 in (Szajnik et al. 2012) cancer cell lines resulted in growth inhibition and increased apoptosis. Increased expression was detected in cancer tissue by immunostaining and was associated with cancer severity. (Kemiläinen et al. 2018) 66 Y.-A. MOON Figure 3. Association of ELOVL5 with colorectal cancer (CRC). (A) ELOVL5 expression in the indicated CRC cell lines (GEO profile GDS4296). (B) TCGA survival data that link ELOVL5 expression level with overall survival of the patients of colon adenocarcinoma shows that the patients with low expression of ELOVL5 (<10th percentile) showed a better survival rate than those with high expression of ELOVL5 (>50th percentile). desaturation, were significantly increased in colon phospholipids, which reflected the increased activities cancer samples compared to the normal tissue. The of ELOVL5/2 and FADS2 in these tumor cells (Hofmanová findings suggest that changes in PUFA contents could et al. 2021). One of the mechanisms that regulates affect cancer cell behavior (Mokhtari et al. 2022). In ELOVL5 activity may be related to genetic variation. A another study, changes in the expression of genes genome-wide analysis found an association between involved in de novo FA and VL-PUFA synthesis were the single nucleotide polymorphisms (SNP) near detected in cultured colon cancer cells. Increased 6p12.1/ELOVL5 gene and survival outcomes in patients expression of fatty acid synthase, stearoyl-CoA desatur- with distant metastatic CRC. The SNP, rs2309489, exhib- ase, FADS2, and ELOVL5 in tumor epithelial cells was cor- ited the strongest association with poor survival rate. related with changes in fatty acid contents of cellular However, the role of genetic variation in CRC has not ANIMAL CELLS AND SYSTEMS 67 been elucidated, and the use of the SNP as a prognostic 2021). Inhibition of the ELOVL5 and IGFBP6 genes in marker has not yet been determined (Phipps et al. 2015). breast cancer cells results in the increased expression Upregulation of enzymes involved in PUFA elongation of matrix metalloproteinase 1 and reduction of intercel- has also been reported in other types of cancer. In a lular contacts. These changes in turn result in a more study that compared gene expression in 74 breast efficient invasion of tumor cells and higher probability cancer tissues with that in normal breast tissues, of increased metastasis (Nikulin et al. 2021). ELOVL1, 5, and 6 were detected as genes that were upre- The studies presented above suggest that the cellular gulated in tumors (Yamashita et al. 2017). VL-PUFA composition and the activities of the synthesis Mechanisms of how ELOVL5 activity affects cancer pathway could play important roles in the development cells have been suggested in a few studies performed and progression of cancer. Although the functions of in prostate cancer, renal cell cancer, and gastric cancer ELOVL5 and its mechanisms in tumorigenesis are still cells. In prostate cancer cells, ELOVL5 expression was unknown, ELOVL5 could be a possible diagnostic and induced by androgen, and increased expression of prognostic marker and a targetable molecule for CRC ELOVL5 in prostate cancer was demonstrated in cul- treatment. tured cells, xenografts, and clinical tumors of prostate FADS2: FADS2, a Δ-6 desaturase, performs the first cancer (Centenera et al. 2021). Upon depletion of rate-limiting step in the endogenous pathway to syn- ELOVL5 in prostate cancer cells, the cells exhibited thesize arachidonic acid from C18 PUFA (Figure 2) morphological and functional changes in the mito- (Tang et al. 2003). The possible involvement of FADS2 chondria, resulting in the excess generation of ROS in the pathogenesis of breast cancer has been to kill the cells (Centenera et al. 2021). In renal cell suggested. Along with increased FDAS2 activity, levels cancer, higher levels of ELOVL5 correlate with poor of metabolites from linoleic acid, such as C18:3, ω-6, clinical prognosis, andELOVL5seemstoleadto C20:3, ω-6, and arachidonic acid, as well as PGE levels, cancer cell proliferation and invasion (Nitta et al. are reportedly increased in cancerous tissue compared 2022). FA changes due to the increased activity of to adjacent noncancerous tissue in breast tumors ELOVL5 have been related to increased cell prolifer- (Pender-Cudlip et al. 2013). These results may lead to ation and invasion (Nitta et al. 2022). Protein kinase similar effects of increased ELOVL5 expression, which B-mammalian target of rapamycin-signal transducer leads to increased arachidonic acid production due to and activator of transcription 3 (AKT-mTOR-STAT3) sig- the greater conversion from linoleic acid. The correlation naling through AKT Ser473 phosphorylation has been between FADS2 expression and PGE levels suggests suggested as a mechanism. However, more studies are that the enzyme activity toward arachidonic acid syn- needed to determine how these lipid changes affect thesis could affect PGE levels and, thus, tumorigenesis signaling pathways. (Pender-Cudlip et al. 2013). Recently, ferroptosis has emerged as a mechanism of HSD17B12: HSD17B12, or β-ketoacyl-CoA reductase, is programed cell death. Ferroptosis is characterized by the enzyme involved in the second step of the FA the accumulation of peroxided VL-PUFAs. Some elongation cycle (Figure 1) (Moon and Horton 2003). gastric cancer cells exhibit differential expression of Therefore, overall FA elongation and cellular FA ELOVL5 and FADS1 through changes in DNA methyl- profiles can be affected by HSD17B12 activity. ation of their promoter regions. ELOVL5 expression is However, the enzyme’s mechanism in tumorigenesis is associated with the levels of cellular arachidonic acid unknown; several studies have reported an association and adrenic acid (C22:4, ω-6) in cancer cells, which between HSD17B12 expression and cancer outcomes. are subjected to lipid peroxidation and ferroptosis Higher expression of HSD17B12 was detected in col- (Lee et al. 2020). As the ferroptosis pathway is a poss- orectal tumor tissues, suggesting a possible correlation ible target forcancertreatment (Diergeetal. 2021), between its activity and CRC. Functional genetic variants ELOVL5 could be a marker for determining whether fer- of HSD17B12 are correlated with the outcome of CRC roptosis-mediated treatment is applicable (Lee et al. (Lin et al. 2020). A Cox regression model that evaluated 2020). The association between ferroptosis sensitiz- the genetic effects on CRC overall survival and pro- ation and differential expression of ELOVL5 needs to gression-free survival revealed that rs10838164 C>T in be determined to indicate its’ therapeutic feasibility in HSD17B12 was significantly associated with an increased CRC. risk of CRC progression and death. The T allele can Contrary to the results presented above, a study increase HSD17B12 expression by enhancing the related the low expression of ELOVL5 and insulin-like binding affinity of transcription factors to promote the growth factor binding protein 6 (IGFBP6) with pro- transcriptional activity of the HSD17B12 gene (Lin et al. nounced metastasis in breast cancer (Nikulin et al. 2020). 68 Y.-A. MOON Changes in the expression of HSD17B12 have been mitochondrial transcription termination factor 1 reported in ovarian and breast cancers (Kemiläinen (MTERF1), and zinc finger protein 606 (ZNF606) genes et al. 2018; Tsachaki et al. 2020). High expression of whose expressions were low (Boot et al. 2017). These HSD17B12, along with increased COX-2 expression, is findings suggest that ELOVL5 expression can be epigen- associated with high-grade epithelial ovarian cancer etically regulated in CRC cells. A survival analysis using (Kemiläinen et al. 2018). The expression level of TCGA data showed that ELOVL5 hypermethylation was HSD17B12 correlated with the severity of ovarian associated with improved overall survival, suggesting cancer, and its expression mimicked COX-2 expression, that low expression of ELOVL5 by DNA hypermethyla- indicating its role in increased arachidonic acid and tion is protective in the progression of CRC progression PGE production during ovarian cancer progression (Boot et al. 2017). The authors also described the corre- (Kemiläinen et al. 2018). High immunoreactivity in lation of ELOVL5 expression with tumor stage and breast cancer has been significantly associated with relapse-free survival. However, a mechanism that can poor prognosis of patients (Nagasaki et al. 2009). When explain this correlation has yet to be elucidated; HSD17B12 was knocked down in cancer cells with high changes in lipogenesis, the downstream transcriptional expression of HSD17B12, cell growth was significantly effect of the MAPK pathway, and its effects on apoptosis inhibited with reduced total amounts of FAs and arachi- have been proposed. donic acid. These changes were completely reversed by the addition of arachidonic acid. HSD17B12 activity may Conclusion be correlated with PG production (Nagasaki et al. 2009). The biological significance and function of 17BHSD12 in The roles of PGE and the responsible enzyme (COX-2) in human cancer remain unknown, and further studies are the stages of CRC have been actively studied. The needed to elucidate its mechanism. enzymes in the VL-PUFA synthesis pathway, including ELOVL5, FADS2, and HSD17B12, can affect cellular ara- chidonic acid level and PGE level, and thus could Epigenetic regulation of ELOVL5 in CRC change the biological activities of cancer cells in multiple Epigenetic regulation is one of the mechanisms that stages. Arachidonic acid and other VL-PUFAs can affect regulate downstream gene expression. Approximately tumorigenesis in PGE -independent manners as well, 70% of genes contain CpG islands in their promoters including stabilization of β-catenine, ferroptosis, ROS (Saxonov et al. 2006; Deaton and Bird 2011). While generation, regulation of transcription factors, and de unmethylated regions usually serve as transcriptional novo lipogenesis. Recent studies have revealed an initiation sites, their methylation can form heterochro- association between the activities of enzymes synthesiz- matin that inhibits the interaction with transcription ing VL-PUFA and tumorigenesis and cancer progression, factors or chromatin remodelers, leading to the inhi- although the mechanisms are still unknown. More bition of downstream gene expression (Saxonov et al. studies are needed to elucidate the role of these 2006; Deaton and Bird 2011). Many tumors exhibit enzymes and further their use as diagnostic and prog- changes in the methylation status of CpG islands nostic markers, and as therapeutic targets for CRC. during tumorigenesis (Paweł and Maria Małgorzata 2022). In a subset of colorectal tumors, an exceptionally high frequency of methylation of some CpG islands has Disclosure statement been described and categorized as a ‘CpG island methy- No potential conflict of interest was reported by the author(s). lator phenotype (CIMP)’, where BRAF mutations are present in most cases (Ogino et al. 2011; Boot et al. 2017). CIMP is one of the mechanisms that lead to chro- Funding matin instability and microsatellite instability during This work was supported by The National Research Foundation tumorigenesis of CRC (Ogino et al. 2011). of Korea [grant number 2021R1A2C1012480]. Methylation-associated transcriptional repression has emerged as a mechanism that inhibits the expression of ELOVL5 in CRC cell lines (Boot et al. 2017). When DNA References methylation and gene expression profiles were gener- Bae S, Kim MK, Kim HS, Moon YA. 2020. 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Journal
Animal Cells and Systems
– Taylor & Francis
Published: Dec 11, 2023
Keywords: colorectal cancer; polyunsaturated fatty acid; ELOVL5; FADS2; arachidonic acid
