Intestinal PPARα Protects Against Colon Carcinogenesis via Regulation of Methyltransferases DNMT1 and PRMT6

Luo, Yuhong; Xie, Cen; Brocker, Chad; Fan, Jia; Wu, Xuan; Feng, Lijin; Wang, Qiong; Zhao, Jie; Lu, Dasheng; Tandon, Mayank; Cam, Maggie; Krausz, Kristopher W.; Liu, Weiwei; Gonzalez, Frank J.

doi:10.1053/j.gastro.2019.05.057

Cited by 119 publications

(91 citation statements)

References 51 publications

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“…Moreover, phthalates have been reported to bind to and modulate the activity of nuclear hormone receptors, including peroxisome proliferator-activated receptors (PPARs), 85 , 86 which function in part through regulation of DNAm. 87 , 88 Studies to determine the sex-specific mechanistic basis for DEHP-induced perturbations in cardiac DNAm are currently underway.…”

Section: Discussionmentioning

confidence: 99%

Sex-Specific Programming of Cardiac DNA Methylation by Developmental Phthalate Exposure

et al. 2020

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Phthalate plasticizers are ubiquitous chemicals linked to several cardiovascular diseases in animal models and humans. Despite this, the mechanisms by which phthalate exposures cause adverse cardiac health outcomes are unclear. In particular, whether phthalate exposures during pregnancy interfere with normal developmental programming of the cardiovascular system, and the resulting implications this may have for long-term disease risk, are unknown. Recent studies suggest that the effects of phthalates on metabolic and neurobehavioral outcomes are sex-specific. However, the influence of sex on cardiac susceptibility to phthalate exposures has not been investigated. One mechanism by which developmental exposures may influence long-term health is through altered programming of DNA methylation. In this work, we utilized an established mouse model of human-relevant perinatal exposure and enhanced reduced representation bisulfite sequencing to investigate the long-term effects of diethylhexyl phthalate (DEHP) exposure on DNA methylation in the hearts of adult male and female offspring at 5 months of age (n = 5-7 mice per sex and exposure). Perinatal DEHP exposure led to hundreds of sex-specific, differentially methylated cytosines (DMCs) and differentially methylated regions (DMRs) in the heart. Pathway analysis of DMCs revealed enrichment for several pathways in females, including insulin signaling, regulation of histone methylation, and tyrosine phosphatase activity. In males, DMCs were enriched for glucose transport, energy generation, and developmental programs. Notably, many sex-specific genes differentially methylated with DEHP exposure in our mouse model were also differentially methylated in published data of heart tissues collected from human heart failure patients. Together, these data highlight the potential role for DNA methylation in DEHP-induced cardiac effects and emphasize the importance of sex as a biological variable in environmental health studies.

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Section: Discussionmentioning

confidence: 99%

Sex-Specific Programming of Cardiac DNA Methylation by Developmental Phthalate Exposure

et al. 2020

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“…All these results indicated that GRIK1 may act as a tumor suppressor in vivo. However, the limitations of the present study were the lack of mechanistic investigations and additional animal tumor models, such as the immune-competent transgenic model (30). Minbay et al (31) reported that homomeric or heteromeric functional receptor channels were formed through the combination of different ionotropic glutamate receptor subunits in red nucleus neurons in normal adult female Sprague-Dawley rats.…”

Section: Discussionmentioning

confidence: 84%

Glutamate receptor ionotropic, kainate 1 serves as a novel tumor suppressor of colorectal carcinoma and predicts clinical prognosis

et al. 2020

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Colorectal cancer (CRC) is one of the most malignant cancers worldwide. However, the mechanisms of initiation and development of CRC are still largely unclear. The present study aimed to investigate the biological function and prognosis of glutamate receptor ionotropic, kainate 1 (GRIK1) in CRC. GRIK1 expression levels were analyzed in tissue microarrays containing 80 primary CRC samples using immunohistochemistry (IHC). The association between GRIK1 expression levels, clinicopathological factors and the prognosis was also investigated using Spearman's correlation analysis and Kaplan-Meier analysis, respectively. After genetic knockdown or overexpression of GRIK1, invasion/migration assays, proliferation assay, soft agar/colony formation assays, western blotting, reverse transcription-quantitative PCR and tumor xenograft models were used to investigate the function of GRIK1 both in vitro in two CRC cell lines, HCT116 and SW620, and in vivo. The results revealed that the expression levels of GRIK1 were significantly downregulated in CRC samples. Furthermore, IHC analysis indicated that the downregulated expression levels of GRIK1 were significantly associated with lymph node status and tumor size. In addition, patients with CRC with low GRIK1 expression levels demonstrated a consistently poor overall survival. The overexpression of GRIK1 inhibited the proliferation, colony formation, migration, invasion and epithelial-mesenchymal transition of HCT116 cells in vitro. In contrast, the genetic knockdown of GRIK1 promoted the proliferative, colony forming, migratory and invasive abilities of SW620 cells in vitro. Moreover, the overexpression of GRIK1 inhibited tumor growth, and liver and lung metastasis of CRC in vivo. In conclusion, the findings of the present study suggested that GRIK1 may serve as a tumor suppressor in CRC, and upregulated expression levels of GRIK1 may predict an improved prognosis for patients with CRC.

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“…The three isotypes of peroxisome proliferator-activated receptors differ in both physiological functions and roles in carcinogenesis. PPAR α , encoded by PPARA, mainly enriches in the liver, kidney, and heart, regulating fatty acid metabolism and mitochondrial biosynthesis [ 25 ]. In addition to its endogenous ligands (fatty acids), PPAR α responds to the PPAR α agonists (synthetic fibrates), such as fenofibrate and gemfibrozil, which have been working well in the treatment for hypolipidemic diseases [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

The Role of Peroxisome Proliferator-Activated Receptors (PPARs) in Pan-Cancer

Huang

Zhang

et al. 2020

PPAR Research

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Peroxisome proliferator-activated receptors (PPARs) are members of nuclear transcription factors. The functions of the PPAR family (PPARA, PPARD, and PPARG) and their coactivators (PPARGC1A and PPARGC1B) in maintenance of lipid and glucose homeostasis have been unveiled. However, the roles of PPARs in cancer development remain elusive. In this work, we made use of 11,057 samples across 33 TCGA tumor types to analyze the relationship between PPAR transcriptional expression and tumorigenesis as well as drug sensitivity. We performed multidimensional analyses on PPARA, PPARG, PPARD, PPARGC1A, and PPARGC1B, including differential expression analysis in pan-cancer, immune subtype analysis, clinical analysis, tumor purity analysis, stemness correlation analysis, and drug responses. PPARs and their coactivators expressed differently in different types of cancers, in different immune subtypes. This analysis reveals various expression patterns of the PPAR family at a level of pan-cancer and provides new clues for the therapeutic strategies of cancer.

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Intestinal PPARα Protects Against Colon Carcinogenesis via Regulation of Methyltransferases DNMT1 and PRMT6

Cited by 119 publications

References 51 publications

Sex-Specific Programming of Cardiac DNA Methylation by Developmental Phthalate Exposure

Sex-Specific Programming of Cardiac DNA Methylation by Developmental Phthalate Exposure

Glutamate receptor ionotropic, kainate 1 serves as a novel tumor suppressor of colorectal carcinoma and predicts clinical prognosis

The Role of Peroxisome Proliferator-Activated Receptors (PPARs) in Pan-Cancer

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