Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors
Pan Pan
Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
Search for more papers by this authorKiyoko Oshima
Department of Pathology, John Hopkins University, Baltimore, MD
Search for more papers by this authorYi-Wen Huang
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI
Search for more papers by this authorKimberle A. Agle
Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
Search for more papers by this authorWilliam R. Drobyski
Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
Search for more papers by this authorXiao Chen
Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
Search for more papers by this authorJianying Zhang
Center for Biostatistics, The Ohio State University, Columbus, OH
Search for more papers by this authorMartha M. Yearsley
Department of Pathology, Ohio State University, Columbus, OH
Search for more papers by this authorCorresponding Author
Jianhua Yu
Division of Hematology, Department of Internal Medicine, College of Medicine, Comprehensive Cancer Center and The James Cancer Hospital, The Ohio State University, Columbus, OH
Correspondence to: Li-Shu Wang, Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, RM C4930, 8701 Watertown Plank Rd, Milwaukee, WI, 53226, USA, Tel.: 414-955-2827, Fax: 414-955-6059, Email: [email protected]; or Jianhua Yu, Division of Hematology, Department of Internal Medicine, College of Medicine, Comprehensive Cancer Center and The James Cancer Hospital, The Ohio State University, Columbus, OH, USA, Email: [email protected]Search for more papers by this authorCorresponding Author
Li-Shu Wang
Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, RM C4930, 8701 Watertown Plank Rd, Milwaukee, WI, 53226
Correspondence to: Li-Shu Wang, Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, RM C4930, 8701 Watertown Plank Rd, Milwaukee, WI, 53226, USA, Tel.: 414-955-2827, Fax: 414-955-6059, Email: [email protected]; or Jianhua Yu, Division of Hematology, Department of Internal Medicine, College of Medicine, Comprehensive Cancer Center and The James Cancer Hospital, The Ohio State University, Columbus, OH, USA, Email: [email protected]Search for more papers by this authorPan Pan
Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
Search for more papers by this authorKiyoko Oshima
Department of Pathology, John Hopkins University, Baltimore, MD
Search for more papers by this authorYi-Wen Huang
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI
Search for more papers by this authorKimberle A. Agle
Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
Search for more papers by this authorWilliam R. Drobyski
Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
Search for more papers by this authorXiao Chen
Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
Search for more papers by this authorJianying Zhang
Center for Biostatistics, The Ohio State University, Columbus, OH
Search for more papers by this authorMartha M. Yearsley
Department of Pathology, Ohio State University, Columbus, OH
Search for more papers by this authorCorresponding Author
Jianhua Yu
Division of Hematology, Department of Internal Medicine, College of Medicine, Comprehensive Cancer Center and The James Cancer Hospital, The Ohio State University, Columbus, OH
Correspondence to: Li-Shu Wang, Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, RM C4930, 8701 Watertown Plank Rd, Milwaukee, WI, 53226, USA, Tel.: 414-955-2827, Fax: 414-955-6059, Email: [email protected]; or Jianhua Yu, Division of Hematology, Department of Internal Medicine, College of Medicine, Comprehensive Cancer Center and The James Cancer Hospital, The Ohio State University, Columbus, OH, USA, Email: [email protected]Search for more papers by this authorCorresponding Author
Li-Shu Wang
Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, RM C4930, 8701 Watertown Plank Rd, Milwaukee, WI, 53226
Correspondence to: Li-Shu Wang, Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, RM C4930, 8701 Watertown Plank Rd, Milwaukee, WI, 53226, USA, Tel.: 414-955-2827, Fax: 414-955-6059, Email: [email protected]; or Jianhua Yu, Division of Hematology, Department of Internal Medicine, College of Medicine, Comprehensive Cancer Center and The James Cancer Hospital, The Ohio State University, Columbus, OH, USA, Email: [email protected]Search for more papers by this authorAbstract
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.
Abstract
What's new?
Free fatty acid receptor 2 (FFAR2) is involved in colonic inflammation. However, it remains unclear whether FFAR2 is an epigenetic regulator that suppresses colon tumorigenesis. This study suggests that loss of FFAR2 epigenetically promotes colon cancer development. The authors found in FFAR2-deficient mice that the downstream cAMP–PKA–CREB–HDAC pathway was enhanced. H3K27me3 and H3K4me3 histone marks differentially bound onto the promoter regions of inflammation suppressors, resulting in their lower expression. More neutrophils infiltrated into tumors and colonic lamina propria. FFAR2 is required for butyrate, a natural ligand of FFAR2, to suppress HDAC expression and hypermethylation of inflammation suppressors.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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| ijc31366-sup-0001-suppinfo01.tif1.4 MB | Supplementary Figure 1 |
| ijc31366-sup-0002-suppinfo02.tif405.4 KB | Supplementary Figure 2 |
| ijc31366-sup-0003-suppinfo03.tif75.1 KB | Supplementary Figure 3 |
| ijc31366-sup-0004-suppinfo04.tif780.5 KB | Supplementary Figure 4 |
| ijc31366-sup-0005-suppinfo05.tif146 KB | Supplementary Figure 5 |
| ijc31366-sup-0006-suppinfo06.tif875.6 KB | Supplementary Figure 6 |
| ijc31366-sup-0007-suppinfo07.docx16.8 KB | Supplementary Table 1 |
| ijc31366-sup-0008-suppinfo08.docx15.1 KB | Supplementary Information |
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