Aging related methylation influences the gene expression of key control genes in colorectal cancer and adenoma

Abstract

AIMTo analyze colorectal carcinogenesis and age-related DNA methylation alterations of gene sequences associated with epigenetic clock CpG sites.METHODSIn silico DNA methylation analysis of 353 epigenetic clock CpG sites published by Steve Horvath was performed using methylation array data for a set of 123 colonic tissue samples [64 colorectal cancer (CRC), 42 adenoma, 17 normal; GEO accession number: GSE48684]. Among the differentially methylated age-related genes, secreted frizzled related protein 1 (SFRP1) promoter methylation was further investigated in colonic tissue from 8 healthy adults, 19 normal children, 20 adenoma and 8 CRC patients using bisulfite-specific PCR followed by methylation-specific high resolution melting (MS-HRM) analysis. mRNA expression of age-related “epigenetic clock” genes was studied using Affymetrix HGU133 Plus2.0 whole transcriptome data of 153 colonic biopsy samples (49 healthy adult, 49 adenoma, 49 CRC, 6 healthy children) (GEO accession numbers: GSE37364, GSE10714, GSE4183, GSE37267). Whole promoter methylation analysis of genes showing inverse DNA methylation-gene expression data was performed on 30 colonic samples using methyl capture sequencing.RESULTSFifty-seven age-related CpG sites including hypermethylated PPP1R16B, SFRP1, SYNE1 and hypomethylated MGP, PIPOX were differentially methylated between CRC and normal tissues (P < 0.05, Δβ ≥ 10%). In the adenoma vs normal comparison, 70 CpG sites differed significantly, including hypermethylated DKK3, SDC2, SFRP1, SYNE1 and hypomethylated CEMIP, SPATA18 (P < 0.05, Δβ ≥ 10%). In MS-HRM analysis, the SFRP1 promoter region was significantly hypermethylated in CRC (55.0% ± 8.4 %) and adenoma tissue samples (49.9% ± 18.1%) compared to normal adult (5.2% ± 2.7%) and young (2.2% ± 0.7%) colonic tissue (P < 0.0001). DNA methylation of SFRP1 promoter was slightly, but significantly increased in healthy adults compared to normal young samples (P < 0.02). This correlated with significantly increased SFRP1 mRNA levels in children compared to normal adult samples (P < 0.05). In CRC tissue the mRNA expression of 117 age-related genes were changed, while in adenoma samples 102 genes showed differential expression compared with normal colonic tissue (P < 0.05, logFC > 0.5). The change of expression for several genes including SYNE1, CLEC3B, LTBP3 and SFRP1, followed the same pattern in aging and carcinogenesis, though not for all genes (e.g., MGP).CONCLUSIONSeveral age-related DNA methylation alterations can be observed during CRC development and progression affecting the mRNA expression of certain CRC- and adenoma-related key control genes.

Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

“…Aging is one of the largest risk factors of carcinogenesis [ 338 ], and there is growing evidence that aging-associated changes in DNA methylation status are closely related to the occurrence of cancer [ 339 , 340 , 341 , 342 ]. Given the many biological activities of polyamines ( Table 1 ) that may inhibit aging-associated pathological processes, including the progression of aberrant DNA methylation, and the experimental findings showing that increased polyamine intake extended animal lifespans, it is reasonable to assume that increased polyamine intake may suppress neoplastic diseases.…”

Implications of Epigenetic Drift in Colorectal Neoplasia

“…Although colorectal cancer genomes have been extensively profiled for somatic mutations, chromosomal abnormalities, and epigenetic alterations (3,9), little is known about the dynamics of the carcinogenic process, including the sojourn time distribution from the time when a premalignant founder cell is born to when the descendent cancer becomes clinically identifiable (13). Here, we aim to better understand these dynamics and the role of epigenetic drift in the colon and rectum as an indicator of tissue aging and its potential phenotypic effects in colorectal neoplasia (14)(15)(16).…”

CLEC3B as a potential diagnostic and prognostic biomarker in lung cancer and association with the immune microenvironment

“…Tetranectin plays a role in extracellular proteolysis by inducing plasminogen activation, which is associated with tumor invasion and metastasis [8,[10][11][12][13]. Moreover, CLEC3B has been reported in multiple cancers, including hepatocellular carcinoma, ovarian cancer, and oral squamous cell carcinoma, but a large number of in-depth studies are still needed to elucidate the molecular mechanism and specific function of CLEC3B in cancer progression [8,[14][15][16][17][18][19]. So far, research on CLEC3B has been very limited.…”