Association of aberrant DNA methylation in Apcmin/+ mice with the epithelial-mesenchymal transition and Wnt/β-catenin pathways: genome-wide analysis using MeDIP-seq

Guo, Yue; Lee, Jong-Hun; Shu, Limin; Huang, Ying; Li, Wenji; Zhang, Chengyue; Yang, Anne Yuqing; Boyanapalli, Sarandeep S.S.; Perekatt, Ansu O.; Hart, Ronald P.; Verzi, Michael P.; Kong, Ah‐Ng Tony

doi:10.1186/s13578-015-0013-2

Cited by 10 publications

(8 citation statements)

References 65 publications

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“…Thus, our data do not support methylation of the APC promoter as a ‘second hit' in one-hit APC tumours. This agrees with several recently published studies showing that promoter methylation in APC plays an insignificant role in substituting for truncating mutations 44 45 . Collectively, we have identified a significant number of tumours harbouring one-hit APC mutations, many of which retained WNT activation that could not be explained by a few possible ‘second-hit' mechanisms.…”

Section: Discussionsupporting

confidence: 93%

A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC

Yang²,

et al. 2016

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Colorectal cancer (CRC) is a highly heterogeneous disease, for which prognosis has been relegated to clinicopathologic staging for decades. There is a need to stratify subpopulations of CRC on a molecular basis to better predict outcome and assign therapies. Here we report targeted exome-sequencing of 1,321 cancer-related genes on 468 tumour specimens, which identified a subset of 17 genes that best classify CRC, with APC playing a central role in predicting overall survival. APC may assume 0, 1 or 2 truncating mutations, each with a striking differential impact on survival. Tumours lacking any APC mutation carry a worse prognosis than single APC mutation tumours; however, two APC mutation tumours with mutant KRAS and TP53 confer the poorest survival among all the subgroups examined. Our study demonstrates a prognostic role for APC and suggests that sequencing of APC may have clinical utility in the routine staging and potential therapeutic assignment for CRC.

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Section: Discussionsupporting

confidence: 93%

A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC

Yang²,

et al. 2016

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“…Our previous studies using DSS‐induced colitis model showed hypermethylation of the promoter region of sfrp1 and dkk3 , suggesting their protective role against colon inflammation . Consistently, sfrp1 and dkk3 were hypermethylated in human CRC and in Apc Min/+ mice . Overexpression of DKK3 suppressed proliferation and invasion, induced apoptosis, and reduced the β‐catenin accumulation in colon cancer cells .…”

Section: Discussionmentioning

confidence: 54%

“…15 Consistently, sfrp1 and dkk3 were hypermethylated in human CRC 25,26 and in Apc Min/1 mice. 27 Overexpression of DKK3 suppressed proliferation and invasion, induced apoptosis, and reduced the b-catenin accumulation in colon cancer cells. 28 In addition, SOCS1 is a suppressor of cytokine signaling, and it has been reported to inhibit the reactive oxygen species (ROS)-induced epithelial-mesenchymal transition of colon cancer cells.…”

Section: Discussionmentioning

confidence: 99%

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

Pan

Oshima²,

Huang

et al. 2018

Intl Journal of Cancer

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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 Apc and the azoxymethane (AOM)-treated mice. Our results showed that FFAR2 deficiency promotes the development of colon adenoma in the Apc /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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“…We found no evidence of reduced 5mC levels in Tumours relative to WT or NAdj samples. Recent genomewide analyses have indeed shown equal gains and losses of methylation at regions with differential methylation between Apc Min/+ tumours and normal tissue 38 . In addition, we have previously shown that 5mC levels are progressively reduced from normal tissue to adenoma to adenocarcinoma 37 , suggesting that marked genome-wide changes observed with malignant progression have not taken place in the more benign Apc Min/+ intraepithelial adenomas.…”

Section: Discussionmentioning

confidence: 99%

ApcMin/+ tumours and normal mouse small intestines show linear metabolite concentration and DNA cytosine hydroxymethylation gradients from pylorus to colon

Madhu

Uribe-Lewis

Bachman

et al. 2020

Sci Rep

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Topographical variations of metabolite concentrations have been reported in the duodenum, jejunum and ileum of the small intestine, and in human intestinal tumours from those regions, but there are no published metabolite concentrations measurements correlated with linear position in the mouse small intestine or intestinal tumours. Since DNA methylation dynamics are influenced by metabolite concentrations, they too could show linear anatomical variation. We measured metabolites by HR-MAS 1 H NMR spectroscopy and DNA cytosine modifications by LC/MS, in normal small intestines of C57BL/6J wild-type mice, and in normal and tumour samples from Apc Min/+ mice. Wild-type mouse intestines showed approximately linear, negative concentration gradations from the pylorus (i.e. the junction with the stomach) of alanine, choline compounds, creatine, leucine and valine. Apc Min/+ mouse tumours showed negative choline and valine gradients, but a positive glycine gradient. 5-Hydroxymethylcytosine showed a positive gradient in the tumours. The linear gradients we found along the length of the mouse small intestine and in tumours contrast with previous reports of discrete concentration changes in the duodenum, jejunum and ileum. To our knowledge, this is also the first report of a systematic measurement of global levels of DNA cytosine modification in wild-type and Apc Min/+ mouse small intestine.

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Association of aberrant DNA methylation in Apcmin/+ mice with the epithelial-mesenchymal transition and Wnt/β-catenin pathways: genome-wide analysis using MeDIP-seq

Cited by 10 publications

References 65 publications

A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC

A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC

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

ApcMin/+ tumours and normal mouse small intestines show linear metabolite concentration and DNA cytosine hydroxymethylation gradients from pylorus to colon

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