Obesity-Associated Differentially Methylated Regions in Colon Cancer

Abstract

Obesity with adiposity is a common disorder in modern days, influenced by environmental factors such as eating and lifestyle habits and affecting the epigenetics of adipose-based gene regulations and metabolic pathways in colorectal cancer (CRC). We compared epigenetic changes of differentially methylated regions (DMR) of genes in colon tissues of 225 colon cancer cases (154 non-obese and 71 obese) and 15 healthy non-obese controls by accessing The Cancer Genome Atlas (TCGA) data. We applied machine-learning-based analytics including generalized regression (GR) as a confirmatory validation model to identify the factors that could contribute to DMRs impacting colon cancer to enhance prediction accuracy. We found that age was a significant predictor in obese cancer patients, both alone (p = 0.003) and interacting with hypomethylated DMRs of ZBTB46, a tumor suppressor gene (p = 0.008). DMRs of three additional genes: HIST1H3I (p = 0.001), an oncogene with a hypomethylated DMR in the promoter region; SRGAP2C (p = 0.006), a tumor suppressor gene with a hypermethylated DMR in the promoter region; and NFATC4 (p = 0.006), an adipocyte differentiating oncogene with a hypermethylated DMR in an intron region, are also significant predictors of cancer in obese patients, independent of age. The genes affected by these DMR could be potential novel biomarkers of colon cancer in obese patients for cancer prevention and progression.

Epigenetic modifications in obesity‐associated diseases

“…40 In tumors of obese patients with colon cancer, the promoter of oncogene histone linker 1 with histone H3.1 (HIST1H3I) is hypomethylated, while the promoter of tumor suppressor gene Slit-Robo Rho GTPase-activating protein 2C (SRGAP2C) is hypermethylated. 41 Additionally, the intron of oncogene nuclear factor of activated T-cells cytoplasmic 4 (NFATC4) demonstrates hypermethylation. 41 The alterations in gene expression resulting from differential methylation regions will contribute to the diagnosis of obesity-associated cancers.…”

“…41 Additionally, the intron of oncogene nuclear factor of activated T-cells cytoplasmic 4 (NFATC4) demonstrates hypermethylation. 41 The alterations in gene expression resulting from differential methylation regions will contribute to the diagnosis of obesity-associated cancers. Nonalcoholic steatohepatitis (NASH) is highly correlated with overnutrition and IR.…”

“…For instance, obesity‐induced inflammation led to hypomethylation of the promoter regions of oncogenes such as Nanog homeobox, POU class 5 homeobox 1 (POU5F1), and MYC proto‐oncogene (MYC) in colon cells, which may eventually cause colon cancer 40 . In tumors of obese patients with colon cancer, the promoter of oncogene histone linker 1 with histone H3.1 (HIST1H3I) is hypomethylated, while the promoter of tumor suppressor gene Slit‐Robo Rho GTPase‐activating protein 2C (SRGAP2C) is hypermethylated 41 . Additionally, the intron of oncogene nuclear factor of activated T‐cells cytoplasmic 4 (NFATC4) demonstrates hypermethylation 41 .…”

Molecular Mechanisms of Western Diet-Induced Obesity and Obesity-Related Carcinogenesis—A Narrative Review

“…Obesity results in epigenetic alterations such as DNA methylation, which has been correlated with the future development of CRC and breast cancer [ 145 , 146 , 147 , 148 , 149 ]. The other main types of epigenetic changes include histone modifications and non-coding mRNA interference.…”

“…DMR can affect the expression of genes involved in DNA repair, cell cycle regulation, cell proliferation and apoptosis, extracellular matrix, Wnt signalling, hormonal signalling and metabolism. DNA hypermethylation increases the risk of abnormal cell function and growth, predisposing individuals to develop chronic diseases, obesity and cancer [ 146 ]. Aberrant DNA methylation can result from the consumption of a high-saturated-fat diet and obesity and be reduced by dietary intervention and physical exercise [ 149 ].…”