Temporal DNA methylation pattern and targeted therapy in colitis-associated cancer

Abstract

DNA methylation plays a crucial role in the pathogenesis of various diseases, including colorectal cancer (CRC). However, the global and temporal DNA methylation pattern during initiation and progression of colitis-associated cancer (CAC) are still unknown, including the potential therapeutic strategy of targeting methylation for CAC. In the present study, the global DNA methylation pattern was determined at different time points during CAC using DNA methylation sequencing, followed by the Starburst plot integrating alterations and potential functional prediction analysis. After demonstrating the regulatory role of DNA methyltransferases (DNMTs) on the expression of hub-genes in CRC cells, DNMT inhibitors were administered to treat CAC mice. Our results indicated that 811 genes were hypermethylated at different time points during initiation and progression of CAC. Genes that were downregulated and hypermethylated during CAC, including hub-genes BAD and inositol polyphosphate phosphatase-like 1 (INPPL1), were involved in MAPK signaling pathways, kit receptor signaling pathways, apoptosis and EGF/EGFR signaling pathways. Upregulated DNMTs (DNMT1, DNMT3A and DNMT3B) mediated downregulation and hypermethylation of BAD and INPPL1 in CAC and CRC cells. Low doses of DNMT inhibitors (decitabine (DAC) and azacitidine (AZA)) exerted efficient antitumor effects in CAC, accompanied with upregulation of BAD and INPPL1 expression, and apoptosis induction. In summary, the present study demonstrates the temporal DNA methylation pattern during CAC and provides a novel therapeutic strategy for treating this disease.

IUSMMT: Survival mediation analysis of gene expression with multiple DNA methylation exposures and its application to cancers of TCGA

“…This specificity largely reflects the inter-tumor heterogeneity of the transcriptomic influence on cancers and the tissue distinction in cancer prognosis [75], implying that mediated pathways of the epigenomic impact vary cancer by cancer although DNA methylation pervasively regulates gene expression. It also has important implication on targeted therapies of precision cancers medicine by intervening DNA methylations [76][77][78].…”

DNA methyltransferase inhibitors combination therapy for the treatment of solid tumor: mechanism and clinical application

“…DNA methylation status sequencing at different time points during colitis-associated cancer (CAC) revealed that 811 genes were hypermethylated at different time points during CAC initiation and progression. These hypermethylated genes, including BAD and inositol polyphosphate phosphatase-like 1 ( INPPL1 ) hub genes, are involved in the MARK and EGF/EGFR pathways [ 112 ]. Tumor growth and drug response were assessed in PANC-1 cells (pancreatic ductal adenocarcinoma, PDAC) after exposure to a noncytotoxic dose of azacitidine.…”

Analysis of 5-Methylcytosine Regulators and DNA Methylation-Driven Genes in Colon Cancer

“…Some research has demonstrated that DNA methylation plays an important role in various biological processes (Luo et al, 2018), such as attaching transcriptional regulation (Poh et al, 2016) and functioning in diverse genomic partitions and developmental stages (Zhou et al, 2018). Li et al (2020) proposed that upregulated writers (DNMT1, DNMT3A, and DNMT3B) facilitated hypermethylation and downregulation of BAD and INPPL1 in colitis-associated cancer. Xu et al (2019) recommended TET2 (eraser) activity as a biomarker to predict the efficacy of anti-PD-1/PD-L1 treatment and patient response and the stimulation of TET2 activity as adjunct immunotherapy for CC.…”