Abstract 5386: Does chemotherapeutics contribute to DNMT1 expression level in colorectal cancer cells

Abstract

Abstract Epigenetic modifications, particularly DNA methylation in selected gene promoters is a pivotal role in the development of colorectal cancer. DNA methylation is considered as one of the most important epigenetic mechanisms and it is catalyzed by DNA methyltransferases (DNMTs). DNMT1 abundance has been frequently seen in colorectal cancers but the reasons are not well understood. We investigated to the effect of chemotherapeutics used in treatment of colorectal cancer on expression of DNMT1 and this effect is achieved over which signalling pathway. In this study, GSK3β; IWP2 for β-catenin) and chemotherapeutics (oxaliplatin, fluorouracil, irinotecan) were detected by WST1. DNMT1 expression level was determinated by real-time PCR; and protein levels of GSK3β, pGSK3β(Ser9), Akt1, pAkt1(Ser473), β-catenin, pβ-catenin(Ser675) and DNMT1 by western blot. Our results indicated taht Akt1 increased the protein level of DNMT1 expression with coordinate transcriptional change via β-catenin pathway. Fluorouracil and irinotecan decreased DNMT1 expression at both transcriptional and translational levels but not oxaliplatin. Oxaliplatin increased DNMT1 expression at mRNA and protein levels. This effect is achieved by specific phosphorylation of β-catenin protein. The results revealed that use of some chemotherapeutic, particularly oxaliplatin, with spesific inhibitors (such as β-catenin inhibitor) in combination led to a reduced DNMT1 expression. Our findings may offer a new approach for determining the molecular effects of β-catenin signal pathway on DNMT1. This may allow us to identify new molecular targets for the treatment of colorectal cancers. However, the results revealed that some chemotherapeutics may contribute the aberration of DNA methylation. Citation Format: NURAY VAROL, SUNA ARIKAN TERZİ, ZAFER SOYLEMEZ, HANDAN YILDIZ, MUJGAN OZDEMİR, MUSTAFA SOLAK. Does chemotherapeutics contribute to DNMT1 expression level in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5386. doi:10.1158/1538-7445.AM2017-5386