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

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

  2. Author Address

    Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Department of Pathology, Huashan Hospital, Fudan University, Shanghai, 200040, China., Central Laboratory and Department of Laboratory Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200070, China; Department of Laboratory Medicine, Shanghai Skin Disease Hospital, Tongji University, Shanghai, 200072, China., Department of Pathology, Shanghai Tenth People 39;s Hospital, Tongji University, Shanghai, 200070, China., CCR Collaborative Bioinformatics Resource, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA., CCR Collaborative Bioinformatics Resource, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Central Laboratory and Department of Laboratory Medicine, Shanghai Tenth People 39;s Hospital, Tongji University, Shanghai, 200070, China; Department of Laboratory Medicine, Shanghai Skin Disease Hospital, Tongji University, Shanghai, 200072, China. Electronic address: hsvivian@tongji.edu.cn., Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: gonzalef@mail.nih.gov.,
    1. Year: 2019
    2. Date: Sep
    3. Epub Date: 2019 05 30
  2. Journal: Gastroenterology
    1. 157
    2. 3
    3. Pages: 744-759.e4
  4. Type of Article: Article
  5. ISSN: 0016-5085
  1. Abstract:

    BACKGROUND & AIMS: Many genetic and environmental factors, including family history, dietary fat, and inflammation, increase risk for colon cancer development. Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a nuclear receptor that regulates systemic lipid homeostasis. We explored the role of intestinal PPAR alpha in colon carcinogenesis. METHODS: Colon cancer was induced in mice with intestine-specific disruption of Ppara (Ppara(Delta IE)), Ppara(fl/fl) (control), and mice with disruption of Ppara that express human PPARA (human PPARA transgenic mice), by administration of azoxymethane with or without dextran sulfate sodium (DSS). Colons were collected from mice and analyzed by immunoblots, quantitative polymerase chain reaction, and histopathology. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses were performed on urine and colons. We used molecular biology and biochemical approaches to study mechanisms in mouse colons, primary intestinal epithelial cells, and colon cancer cell lines. Gene expression data and clinical features of patients with colorectal tumors were obtained from Oncomine, and human colorectal-tumor specimens and adjacent normal tissues were collected and analyzed by immunohistochemistry. RESULTS: Levels of Ppara messenger RNA were reduced in colon tumors from mice. Ppara(Delta IE) mice developed more and larger colon tumors than control mice following administration of azoxymethane, with or without DSS. Metabolomic analyses revealed increases in methylation-related metabolites in urine and colons from Ppara(Delta IE) mice, compared with control mice, following administration of azoxymethane, with or without DSS. Levels of DNA methyltransferase 1 (DNMT1) and protein arginine methyltransferase 6 (PRMT6) were increased in colon tumors from Ppara(Delta IE) mice, compared with colon tumors from control mice. Depletion of PPAR alpha reduced the expression of retinoblastoma protein, resulting in increased expression of DNMT1 and PRMT6. DNMT1 and PRMT6 decreased expression of the tumor suppressor genes Cdkn1a (P21) and Cdkn1b (p27) via DNA methylation and histone H3R2 dimethylation-mediated repression of transcription, respectively. Fenofibrate protected human PPARA transgenic mice from azoxymethane and DSS-induced colon cancer. Human colon adenocarcinoma specimens had lower levels of PPARA and retinoblastoma protein and higher levels of DNMT1 and PRMT6 than normal colon tissues. CONCLUSIONS: Loss of PPAR alpha from the intestine promotes colon carcinogenesis by increasing DNMT1-mediated methylation of P21 and PRMT6-mediated methylation of p27 in mice. Human colorectal tumors have lower levels of PPARA messenger RNA and protein than nontumor tissues. Agents that activate PPAR alpha might be developed for chemoprevention or treatment of colon cancer.

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External Sources

  1. View Full Text
  2. DOI: 10.1053/j.gastro.2019.05.057
  3. PMID: 31154022
  4. View record in Web of Science®
  5. WOS: 000481615500029
  6. PII : S0016-5085(19)40975-X

Library Notes

  1. Fiscal Year: FY2018-2019
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