Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors.
Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors.
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FFAR2的缺失通过炎症抑制因子的表观遗传失调促进结肠癌。
DOI：
10.1002/ijc.31366
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发表时间：
2018-08-15
影响因子：
6.4
通讯作者：
Wang LS
中科院分区：
文献类型：
--
作者：
Pan P;Oshima K;Huang YW;Agle KA;Drobyski WR;Chen X;Zhang J;Yearsley MM;Yu J;Wang LS
游离脂肪酸受体 2（FFAR2，也称为 GPR43）由短链脂肪酸 (SCFA)（例如丁酸盐）激活，短链脂肪酸是肠道细菌发酵膳食纤维时产生的。 FFAR2 被认为可以调节结肠炎症，结肠炎症是结肠癌发生的主要危险因素，也与结肠癌发生过程中的表观遗传失调有关。目前的研究评估了 FFAR2 作为表观遗传调节因子是否可以预防结肠癌。为了模拟促进人类结肠癌的轻度炎症，我们用右旋糖酐硫酸钠 (DSS) 治疗小鼠过夜，这避免了过度炎症，但在 ApcMin/+ 和氧化偶氮甲烷 (AOM) 治疗的小鼠中诱导了促进结肠癌发生的轻度炎症。我们的结果表明，FFAR2 缺陷促进 ApcMin/+/DSS 小鼠中结肠腺瘤的发展以及 AOM/DSS 小鼠中腺瘤向腺癌的进展。 FFAR2 的下游 cAMP-PKA-CREB 通路得到增强，导致 FFAR2 缺陷小鼠中组蛋白脱乙酰酶 (HDAC) 过度表达。 ChIP-qPCR 分析显示，H3K27me3 和 H3K4me3 组蛋白标记与炎症抑制因子（例如 sfrp1、dkk3、socs1）启动子区域的差异结合，导致 FFAR2 缺陷小鼠中这些基因的表达降低。此外，更多的中性粒细胞浸润到 FFAR2 缺陷小鼠的肿瘤和结肠固有层中。中性粒细胞的消耗阻止了结肠肿瘤的进展。此外，丁酸需要 FFAR2 来抑制 HDAC 表达和炎症抑制因子的高甲基化。因此，我们的结果表明 FFAR2 是一种表观遗传肿瘤抑制因子，在结肠癌发生的多个阶段发挥作用。
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.
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影响因子：
6
作者：
Kim CH;Park J;Kim M
通讯作者：
Kim M
DOI：
10.1016/s0006-291x(03)00488-1
发表时间：
2003-04-18
影响因子：
3.1
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
7.5
作者：
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