Impact of Genetic and Epigenetic Variations Within the
            <i>FADS</i>
            Cluster on the Composition and Metabolism of Polyunsaturated Fatty Acids in Prostate Cancer

Cui, Tao; Hester, Austin G.; Seeds, Michael C.; Rahbar, Elaheh; Howard, Timothy D.; Sergeant, Susan; Chilton, Floyd H.

doi:10.1002/pros.23205

Cited by 25 publications

(22 citation statements)

References 41 publications

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“…These results are in agreement with our previous studies that demonstrated DNA methylation at CpG sites in the FADS2 promoter region was significantly associated with genotype at rs174537 in human liver tissues [ 10 , 24 ]. In addition, genotype at rs174537 is associated with the level of circulating n-6 LC-PUFAs specifically ARA and ARA/DGLA ratio, in both plasma and serum, which is consistent with previous published studies [ 9 , 31 , 32 ] (Additional file 2 : Figure S1).…”

Section: Resultssupporting

confidence: 91%

“…This study builds upon previous data from our lab and emerging literature by others supporting the notion that SNPs, such as rs174537, and other SNPs in high linkage disequilibrium (LD), and dietary PUFAs can impact the epigenetic regulation of LC-PUFA biosynthesis in humans [ 3 , 5 , 10 , 21 , 24 , 31 , 32 , 34 – 38 ]. The CpG sites located in the FADS2 promoter region not only demonstrated significant ASM, but also displayed strong associations with circulating plasma and serum n-6 LC-PUFAs.…”

Section: Discussionmentioning

confidence: 60%

“…The methylation status of DNA obtained from total leukocytes (cohort 1) and CD4+ cells and saliva (cohort 2) was assessed using pyrosequencing, as previously described [ 31 ]. Based on our previous studies, DNA methylation was quantified at six key CpG sites between FADS1 and FADS2.…”

Section: Methodsmentioning

confidence: 99%

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Allele-specific methylation in the FADS genomic region in DNA from human saliva, CD4+ cells, and total leukocytes

et al. 2018

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BackgroundGenetic variants within the fatty acid desaturase (FADS) gene cluster (human Chr11) are important regulators of long-chain (LC) polyunsaturated fatty acid (PUFA) biosynthesis in the liver and consequently have been associated with circulating LC-PUFA levels. More recently, epigenetic modifications such as DNA methylation, particularly within the FADS cluster, have been shown to affect LC-PUFA levels. Our lab previously demonstrated strong associations of allele-specific methylation (ASM) between a single nucleotide polymorphism (SNP) rs174537 and CpG sites across the FADS region in human liver tissues. Given that epigenetic signatures are tissue-specific, we aimed to evaluate the methylation status and ASM associations between rs174537 and DNA methylation obtained from human saliva, CD4+ cells and total leukocytes derived from whole blood. The goals were to (1) determine if DNA methylation from these peripheral samples would display similar ASM trends as previously observed in human liver tissues and (2) evaluate the associations between DNA methylation and circulating LC-PUFAs.ResultsDNA methylation at six CpG sites spanning FADS1 and FADS2 promoter regions and a putative FADS enhancer region were determined in two Caucasian cohorts of healthy volunteers: leukocytes in cohort 1 (n = 89, median age = 43, 35% male) and saliva and CD4+ cells in cohort 2 (n = 32, median age = 41, 41% male). Significant ASM between rs174537 and DNA methylation at three CpG sites located in the FADS2 promoter region (i.e., chr11:61594865, chr11:61594876, chr11:61594907) and one CpG site in the putative enhancer region (chr11:61587979) were observed with leukocytes. In CD4+ cells, significant ASM was observed at CpG sites chr11:61594876 and chr11:61584894. Genotype at rs174537 was significantly associated with DNA methylation from leukocytes. Similar trends were observed with CD4+ cells, but not with saliva. DNA methylation from leukocytes and CD4+ cells also significantly correlated with circulating omega-6 LC-PUFAs.ConclusionsWe observed significant ASM between rs174537 and DNA methylation at key regulatory regions in the FADS region from leukocyte and CD4+ cells. DNA methylation from leukocytes also correlated with circulating omega-6 LC-PUFAs. These results support the use of peripheral whole blood samples, with leukocytes showing the most promise for future nutrigenomic studies evaluating epigenetic modifications affecting LC-PUFA biosynthesis in humans.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0480-5) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 60%

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Allele-specific methylation in the FADS genomic region in DNA from human saliva, CD4+ cells, and total leukocytes

et al. 2018

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“…In addition to cancer-intrinsic functions, arachidonic acid uptake and synthesis of prostaglandins such as PGE 2 have immunosuppressive functions 51 . Because both adrenic acid and arachidonic acid are present in prostate cancer specimens 56 , the adrenic-to-arachidonic pathway suggests that blocking both arachidonic and adrenic uptake may be required to abolish the immunosuppressive effects of PGE 2 .…”

Section: Resultsmentioning

confidence: 99%

Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

Wang

Ruzzo

2020

Sci Rep

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Spatial heterogeneity is a fundamental feature of the tumor microenvironment (TME), and tackling spatial heterogeneity in neoplastic metabolic aberrations is critical for tumor treatment. Genomescale metabolic network models have been used successfully to simulate cancer metabolic networks. However, most models use bulk gene expression data of entire tumor biopsies, ignoring spatial heterogeneity in the TME. To account for spatial heterogeneity, we performed spatially-resolved metabolic network modeling of the prostate cancer microenvironment. We discovered novel malignantcell-specific metabolic vulnerabilities targetable by small molecule compounds. We predicted that inhibiting the fatty acid desaturase SCD1 may selectively kill cancer cells based on our discovery of spatial separation of fatty acid synthesis and desaturation. We also uncovered higher prostaglandin metabolic gene expression in the tumor, relative to the surrounding tissue. Therefore, we predicted that inhibiting the prostaglandin transporter SLCO2A1 may selectively kill cancer cells. Importantly, SCD1 and SLCO2A1 have been previously shown to be potently and selectively inhibited by compounds such as CAY10566 and suramin, respectively. We also uncovered cancer-selective metabolic liabilities in central carbon, amino acid, and lipid metabolism. Our novel cancer-specific predictions provide new opportunities to develop selective drug targets for prostate cancer and other cancers where spatial transcriptomics datasets are available.Cancer cells reprogram their metabolism to fulfill the energetic and biosynthetic needs of proliferation, invasion and migration 1 . This is exemplified in prostate cancer, the second most common cancer in American men after melanoma 2 . Previous studies have uncovered profound metabolic dysregulation in multiple pathways, particularly in fatty acid and lipid metabolism 3,4 . Discovering novel cancer-specific metabolic aberrations has significant translational applications, because cancer-associated metabolic dysfunctions can be exploited to advance cancer detection (e.g., 18 F-FDG (Fludeoxyglucose) imaging based on elevated glycolysis in cancer 5 ) and treatment (e.g., L-asparaginase in treating acute lymphoblastic leukemia 6 ).Cancer metabolic reprograming is profoundly impacted by spatial heterogeneity, a fundamental feature of the tumor microenvironment (TME) 7 . Heterogeneous distributions of blood vessels and stromal tissues create uneven spatial gradients of nutrients and metabolic byproducts, which significantly shape the phenotypes of many cell types in the TME 8 . Recent technologies, such as spatial transcriptomics 9,10 and Slide-seq 11 have enabled transcriptomic profiling of hundreds of locations within tissue sections with high spatial resolution (2-100 μm), and have been used to study multiple types of malignancies, including prostate cancer, breast cancer, pancreatic cancer, and melanoma 9,10,12-14 . These spatially-resolved datasets provide novel opportunities to dissect spatial metabolic heterogeneity i...

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“…We postulate that these genomic variants, along with high omega-6 PUFA exposure in the modern Western diet, have the capacity to create destructive genetic/epigenetic-dietary PUFA interactions. This, in turn, could have important implications on downstream inflammatory processes and disease states, including hypertension, diabetes, heart disease, and cancer [ 35 , 36 , 45 , 46 ]. Taken together, all of these studies suggest that a “one size fits all” dietary PUFA recommendation may not be appropriate.…”

Section: Discussionmentioning

confidence: 99%

Uncovering the DNA methylation landscape in key regulatory regions within the FADS cluster

Rahbar¹,

Ainsworth²,

Howard³

et al. 2017

PLoS ONE

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Genetic variants near and within the fatty acid desaturase (FADS) cluster are associated with polyunsaturated fatty acid (PUFA) biosynthesis, levels of several disease biomarkers and risk of human disease. However, determining the functional mechanisms by which these genetic variants impact PUFA levels remains a challenge. Utilizing an Illumina 450K array, we previously reported strong allele-specific methylation (ASM) associations (p = 2.69×10−29) between a single nucleotide polymorphism (SNP) rs174537 and DNA methylation of CpG sites located in the putative enhancer region between FADS1 and FADS2, in human liver tissue. However, this array only featured 20 CpG sites within this 12kb region. To better understand the methylation landscape within this region, we conducted bisulfite sequencing of the region between FADS1 and FADS2. Liver tissues from 50 male subjects (27 European Americans, 23 African Americans) were obtained from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study, and used to ascertain the genotype at rs174537 and methylation status across the region of interest. Associations between rs174537 genotype and methylation status of 136 CpG sites were determined. Age-adjusted linear regressions were used to assess ASM associations with rs174537 genotype. The majority of CpG sites (117 out of 136, 86%) exhibited high levels of methylation with the greatest variability observed at three key regulatory regions–the promoter regions for FADS1 and FADS2 and a putative enhancer site between the two genes. Eight CpG sites within the putative enhancer region displayed significant (FDR p <0.05) ASM associations with rs174537. These data support the concept that both genetic and epigenetic factors regulate PUFA biosynthesis, and raise fundamental questions as to how genetic variants such as rs174537 impact DNA methylation in distant regulatory regions, and ultimately the capacity of tissues to synthesize PUFAs.

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Impact of Genetic and Epigenetic Variations Within the FADS Cluster on the Composition and Metabolism of Polyunsaturated Fatty Acids in Prostate Cancer

Cited by 25 publications

References 41 publications

Allele-specific methylation in the FADS genomic region in DNA from human saliva, CD4+ cells, and total leukocytes

Allele-specific methylation in the FADS genomic region in DNA from human saliva, CD4+ cells, and total leukocytes

Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

Uncovering the DNA methylation landscape in key regulatory regions within the FADS cluster

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