Unknown

Dataset Information

0

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


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.

SUBMITTER: Pan P 

PROVIDER: S-EPMC6041131 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Pan Pan P   Oshima Kiyoko K   Huang Yi-Wen YW   Agle Kimberle A KA   Drobyski William R WR   Chen Xiao X   Zhang Jianying J   Yearsley Martha M MM   Yu Jianhua J   Wang Li-Shu LS  

International journal of cancer 20180330 4


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  ...[more]

Similar Datasets

| S-EPMC5354798 | biostudies-literature
| S-EPMC6136879 | biostudies-other
| S-EPMC6445715 | biostudies-literature
2015-06-17 | E-GEOD-57569 | biostudies-arrayexpress
| S-EPMC4119908 | biostudies-literature
| S-EPMC7456070 | biostudies-literature
| S-EPMC6347978 | biostudies-literature
2015-06-17 | E-GEOD-57527 | biostudies-arrayexpress
2015-06-17 | E-GEOD-57533 | biostudies-arrayexpress
2015-06-17 | GSE57569 | GEO