Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors

Pan Pan, Kiyoko Oshima, Yi Wen Huang, Kimberle A. Agle, William R. Drobyski, Xiao Chen, Jianying Zhang, Martha M. Yearsley, Jianhua Yu, Li Shu Wang

Research output: Contribution to journalArticlepeer-review

Abstract

Free fatty acid receptor 2 (FFAR2, also named GPR43), is activated by short-chain fatty acids (SCFAs), such as butyrate, that are produced when gut bacteria ferment dietary fiber. FFAR2 has been suggested to regulate colonic inflammation, which is a major risk factor for the development of colon cancer and is also linked to epigenetic dysregulation in colon carcinogenesis. The current study assessed whether FFAR2, acting as an epigenetic regulator, protects against colon carcinogenesis. To mimic the mild inflammation that promotes human colon cancer, we treated mice with dextran sodium sulfate (DSS) overnight, which avoids excessive inflammation but induces mild inflammation that promotes colon carcinogenesis in the ApcMin/+ and the azoxymethane (AOM)-treated mice. Our results showed that FFAR2 deficiency promotes the development of colon adenoma in the ApcMin/+/DSS mice and the progression of adenoma to adenocarcinoma in the AOM/DSS mice. FFAR2's downstream cAMP–PKA–CREB pathway was enhanced, leading to overexpression of histone deacetylases (HDACs) in the FFAR2-deficient mice. ChIP-qPCR analysis revealed differential binding of H3K27me3 and H3K4me3 histone marks onto the promoter regions of inflammation suppressors (e.g., sfrp1, dkk3, socs1), resulting in decreased expression of these genes in the FFAR2-deficient mice. Also, more neutrophils infiltrated into tumors and colon lamina propria of the FFAR2-deficient mice. Depletion of neutrophils blocked the progression of colon tumors. In addition, FFAR2 is required for butyrate to suppress HDAC expression and hypermethylation of inflammation suppressors. Therefore, our results suggest that FFAR2 is an epigenetic tumor suppressor that acts at multiple stages of colon carcinogenesis.

Original languageEnglish (US)
Pages (from-to)886-896
Number of pages11
JournalInternational Journal of Cancer
Volume143
Issue number4
DOIs
StatePublished - Aug 15 2018

Keywords

  • FFAR2
  • HDAC
  • butyrate
  • colon cancer
  • epigenetics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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