Chronic inflammation induces a novel epigenetic program that is conserved in intestinal adenomas and in colorectal cancer

Published on May 15, 2015in Cancer Research8.378
· DOI :10.1158/0008-5472.CAN-14-3295
Monther Abu-Remaileh15
Estimated H-index: 15
(HUJI: Hebrew University of Jerusalem),
Sebastian Bender23
Estimated H-index: 23
(DKFZ: German Cancer Research Center)
+ 9 AuthorsFrank Lyko52
Estimated H-index: 52
Chronic inflammation represents a major risk factor for tumor formation, but the underlying mechanisms have remained largely unknown. Epigenetic mechanisms can record the effects of environmental challenges on the genome level and could therefore play an important role in the pathogenesis of inflammation-associated tumors. Using single-base methylation maps and transcriptome analyses of a colitis-induced mouse colon cancer model, we identified a novel epigenetic program that is characterized by hypermethylation of DNA methylation valleys that are characterized by low CpG density and active chromatin marks. This program is conserved and functional in mouse intestinal adenomas and results in silencing of active intestinal genes that are involved in gastrointestinal homeostasis and injury response. Further analyses reveal that the program represents a prominent feature of human colorectal cancer and can be used to correctly classify colorectal cancer samples with high accuracy. Together, our results show that inflammatory signals establish a novel epigenetic program that silences a specific set of genes that contribute to inflammation-induced cellular transformation. Cancer Res; 75(10); 2120–30. ©2015 AACR .
Figures & Tables
  • References (49)
  • Citations (49)
📖 Papers frequently viewed together
438 Citations
49 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
#1Chun-Hao Lu (NTU: National Taiwan University)H-Index: 1
#2Wan-Yi Wu (NTU: National Taiwan University)H-Index: 2
Last. Lung-Chih Yu (NTU: National Taiwan University)H-Index: 17
view all 5 authors...
The cell surface sialyl Lewis a (sLe(a)) and sialyl Lewis x (sLe(x)) antigens, which are built on the terminals of glyco-structures called poly-N-acetyllactosamine (LacNAc) chains, have been shown to play a critical role in the metastasis of colon cancer. In the present investigation, expression of the B3GNT7 gene, which encodes a β-1,3-N-acetylglucosaminyltransferase that mainly acts on and extends sulfated poly-LacNAc chains, was found to be markedly suppressed during the oncogenetic processes...
11 CitationsSource
#1Deborah Nejman (HUJI: Hebrew University of Jerusalem)H-Index: 7
#2Ravid Straussman (Weizmann Institute of Science)H-Index: 16
Last. Howard Cedar (HUJI: Hebrew University of Jerusalem)H-Index: 73
view all 7 authors...
De novo methylation of CpG islands is seen in many cancers, but the general rules governing this process are not known. By analyzing DNA from tumors, as well as normal tissues, and by utilizing a range of published data, we have identified a universal set of tumor targets, each with its own "coefficient" of methylation that is largely correlated with its inherent relative ability to recruit polycomb. This pattern is initially formed by a slow process of de novo methylation that occurs during agi...
31 CitationsSource
#1Mira Jeong (BCM: Baylor College of Medicine)H-Index: 27
#2Deqiang Sun (BCM: Baylor College of Medicine)H-Index: 19
Last. Margaret A. Goodell (BCM: Baylor College of Medicine)H-Index: 68
view all 22 authors...
Margaret Goodell and colleagues report genome-wide mapping of 5-methylcytosine and 5-hydroxymethylcytosine in purified mouse hematopoietic stem cells. They identify large regions of low methylation with borders marked by 5-hydroxymethylcytosine. These borders become eroded in the absence of DNA methyltransferase 3a.
178 CitationsSource
#1Eran Elinav (Weizmann Institute of Science)H-Index: 58
#2Roni Nowarski (Yale University)H-Index: 13
Last. Richard A. Flavell (Yale University)H-Index: 210
view all 6 authors...
The role of inflammation in tumorigenesis and tumour progression is increasingly coming into focus, and this Review discusses the current ideas about the mechanisms of inflammation-associated tumorigenesis and the association with the microbiota.
732 CitationsSource
#1Michael J. Ziller (Broad Institute)H-Index: 24
#2Hongcang Gu (Broad Institute)H-Index: 35
Last. Alexander MeissnerH-Index: 77
view all 12 authors...
DNA methylation is a defining feature of mammalian cellular identity and essential for normal development 1,2 . Most cell types, except germ cells and pre-implantation embryos 3–5 , display relatively stable DNA methylation patterns with 70–80% of all CpGs being methylated 6 . Despite recent advances we still have a too limited understanding of when, where and how many CpGs participate in genomic regulation. Here we report the in depth analysis of 42 whole genome bisulfite sequencing (WGBS) data...
795 CitationsSource
#1Nicholas T. Ventham (Western General Hospital)H-Index: 16
#2Nicholas A. Kennedy (Western General Hospital)H-Index: 31
Last. Jack Satsangi (Western General Hospital)H-Index: 78
view all 4 authors...
In the past decade, there have been fundamental advances in our understanding of genetic factors that contribute to the inflammatory bowel diseases (IBDs) Crohn’s disease and ulcerative colitis. The latest international collaborative studies have brought the number of IBD susceptibility gene loci to 163. However, genetic factors account for only a portion of overall disease variance, indicating a need to better explore gene-environment interactions in the development of IBD. Epigenetic factors c...
164 CitationsSource
#1V. A. NaumovH-Index: 7
Last. Vadim M. GovorunH-Index: 32
view all 9 authors...
Illumina’s Infinium HumanMethylation450 BeadChip arrays were used to examine genome-wide DNA methylation profiles in 22 sample pairs from colorectal cancer (CRC) and adjacent tissues and 19 colon tissue samples from cancer-free donors. We show that the methylation profiles of tumors and healthy tissue samples can be clearly distinguished from one another and that the main source of methylation variability is associated with disease status. We used different statistical approaches to evaluate the...
77 CitationsSource
#1Winston Timp (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 22
#2Andrew P. Feinberg (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 103
Feinberg and Timp review cancer-associated epigenetic alterations and propose that epigenetic dysregulation is an initiating force in tumorigenesis that promotes the selection of cancer-associated phenotypes and that can cooperate with genetic alterations, indicating that the gene-centric view of cancer biology is not the whole story.
349 CitationsSource
#1Casey A. Gifford (Broad Institute)H-Index: 13
#2Michael J. Ziller (Broad Institute)H-Index: 24
Last. Alexander Meissner (Broad Institute)H-Index: 77
view all 24 authors...
Differentiation of human embryonic stem cells (hESCs) provides a unique opportunity to study the regulatory mechanisms that facilitate cellular transitions in a human context. To that end, we performed comprehensive transcriptional and epigenetic profiling of populations derived through directed differentiation of hESCs representing each of the three embryonic germ layers. Integration of whole-genome bisulfite sequencing, chromatin immunoprecipitation sequencing, and RNA sequencing reveals uniqu...
293 CitationsSource
#1Wei Xie (Ludwig Institute for Cancer Research)H-Index: 29
#2Matthew D. Schultz (HHMI: Howard Hughes Medical Institute)H-Index: 17
Last. Bing Ren (UCSD: University of California, San Diego)H-Index: 88
view all 42 authors...
Summary Epigenetic mechanisms have been proposed to play crucial roles in mammalian development, but their precise functions are only partially understood. To investigate epigenetic regulation of embryonic development, we differentiated human embryonic stem cells into mesendoderm, neural progenitor cells, trophoblast-like cells, and mesenchymal stem cells and systematically characterized DNA methylation, chromatin modifications, and the transcriptome in each lineage. We found that promoters that...
470 CitationsSource
Cited By49
BACKGROUND: An increasing number of studies have focused on the early diagnostic value of the methylation of RASSF1A and SHOX2 in lung cancer. However, the intricate cellular events related to RASSF1A and SHOX2 in lung cancer are still a mystery. For researchers and clinicians aiming to more profoundly understand the diagnostic value of methylated RASSF1A and SHOX2 in lung cancer, this review will provide deeper insights into the molecular events of RASSF1A and SHOX2 in lung cancer. METHODOLOGY:...
1 CitationsSource
#1John Heath (McGill University)H-Index: 1
#1John J. Heath (MUN: Memorial University of Newfoundland)H-Index: 3
Last. Michael D. Grant (MUN: Memorial University of Newfoundland)H-Index: 13
view all 2 authors...
Aging reflects long-term decline in physiological function and integrity. Changes arise at a variable pace governed by time-dependent and -independent mechanisms that are themselves complex, interdependent and variable. Molecular decay produces inferior cells that eventually dominate over healthy counterparts in tissues they comprise. In a form of biological entropy, progression from molecular through cellular to tissue level degeneration culminates in organ disease or dysfunction, affecting sys...
The link between asbestos exposure and the onset of thoracic malignancies is well established. However epidemiological studies have provided evidences that asbestos may be also involved in the development of gastrointestinal tumors, including intrahepatic cholangiocarcinoma (ICC). In line with this observation, asbestos fibers have been detected in the liver of patients with ICC. Although the exact mechanism still remains unknown, the presence of asbestos fibers in the liver could be explained i...
#1Ihab Ansari (HUJI: Hebrew University of Jerusalem)H-Index: 2
#2Günter Raddatz (DKFZ: German Cancer Research Center)H-Index: 11
Last. Eran Elinav (Weizmann Institute of Science)H-Index: 58
view all 12 authors...
Although much research has been done on the diversity of the gut microbiome, little is known about how it influences intestinal homeostasis under normal and pathogenic conditions. Epigenetic mechanisms have recently been suggested to operate at the interface between the microbiota and the intestinal epithelium. We performed whole-genome bisulfite sequencing on conventionally raised and germ-free mice, and discovered that exposure to commensal microbiota induced localized DNA methylation changes ...
7 CitationsSource
#1Renyi Wu (RU: Rutgers University)H-Index: 13
#2Lujing Wang (RU: Rutgers University)H-Index: 4
Last. Ah-Ng Tony Kong (RU: Rutgers University)H-Index: 59
view all 11 authors...
Colorectal cancer (CRC) is associated with significant morbidity and mortality in the US and worldwide. CRC is the second most common cancer-related death in both men and women globally. Chronic inflammation has been identified as one of the major risk factors of CRC. It may drive genetic and epigenetic/epigenomic alterations, such as DNA methylation, histone modification, and non-coding RNA regulation. Current prevention modalities for CRC are limited and some treatment regimens such as use the...
3 CitationsSource
#1Kensei Nishida (University of Tokushima)H-Index: 20
#2Yuki Kuwano (University of Tokushima)H-Index: 34
Last. Kazuhito Rokutan (University of Tokushima)H-Index: 44
view all 3 authors...
Acquisition of cell migration capacity is an early and essential process in cancer development. The aim of this study was to identify microRNA gene expression networks that induced high migration capacity. Using colon cancer HCT116 cells subcloned by transwell-based migrated cell selection, microRNA array analysis was performed to examine the microRNA expression profile. Promoter activity and microRNA targets were assessed with luciferase reporters. Cell migration capacity was assessed by either...
#1Emily L. Paton (University of Colorado Denver)H-Index: 1
#2Jacqueline A. Turner (University of Colorado Denver)H-Index: 5
Last. Isabel R. Schlaepfer (University of Colorado Denver)H-Index: 17
view all 3 authors...
Overactivation of the mitogen-activated protein kinase (MAPK) pathway is an important driver of many human cancers. First line, FDA-approved therapies targeting MAPK signalling, which include BRAF and MEK inhibitors, have variable success across cancers, and a significant number of patients quickly develop resistance. In recent years, a number of preclinical studies have reported alternative methods of overcoming resistance, which include promoting apoptosis, modulating autophagy, and targeting ...
4 CitationsSource
#1Lijun JinH-Index: 1
#2Wei-Bin Chen (North China University of Science and Technology)H-Index: 1
Last. Zunyi WangH-Index: 1
view all 6 authors...
BACKGROUND Accurate assessment of the prognosis after colorectal cancer surgery is of great significance in patients with colorectal cancer. However, there is no systematic analysis of factors affecting the prognosis of colorectal cancer currently.
1 CitationsSource
#1Haoyu WangH-Index: 2
#2Yurui MaH-Index: 2
Last. Yajun LiangH-Index: 1
view all 7 authors...
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Isoxazoline and isoxazole derivatives represent an important class of five-membered heterocycles, which play a pivotal role in drug discovery. In our previous study, we developed a series of isoxazole derivatives with an efficient method. In this study, we evaluated their effects on tumor cell growth. HCT116 cells were treated with isoxazole derivatives; an cholecystokinin octapeptide (CCK-8) assay was used to calcula...
2 CitationsSource
#1Zhenhua Yang (SHU: Shanghai University)H-Index: 1
Last. Guang Ji (SHU: Shanghai University)H-Index: 16
view all 3 authors...
: Molecular mechanisms associated with inflammation-promoted tumorigenesis have become an important topic in cancer research. Various abnormal epigenetic changes, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA regulation, occur during the transformation of chronic inflammation into colorectal cancer (CRC). These changes not only accelerate transformation but also lead to cancer progression and metastasis by activating carcinogenic signaling pathways. The...
5 CitationsSource