Abstract
Abstract Leiomyosarcomas (LMS) are aggressive mesenchymal tumors of smooth muscle origin. Understanding the molecular alterations associated with LMS is needed to identify potential therapeutic targets. Epigenetic alterations such as hypermethylation of gene promoter regions with associated transcriptional silencing is a hallmark of most cancers. Epigenetic reprograming is fundamentally linked to tumor initiation, progression and metastasis. Frequent epigenetic alterations have been observed in LMS. Epigenetic drugs such as DNA methyltransferase inhibitors (DNMTi) have been used to reverse aberrant DNA methylation and restore expression of silenced genes. Our previous studies using DNMTi, including guadecitabine, have shown that DNMTi treatment has anti-proliferative and pro-apoptotic effects in in vitro and in vivo models of LMS. Our goal was to characterize the methylation changes following guadecitabine treatment of the leiomyosarcoma cell line SK-UT1. SK-UT1 cells were treated with guadecitabine (0.05 µM-0.1 µM) and methylation was determined using Illumina 450K platform. We filtered the promoter CpG island regions that respond to guadecitabine treatment and were associated with decreased methylation compared to untreated SK-UT1 control (p≤0.05, Δβ≥0.15). In order to assess the relevance of these differentially methylated regions, we compared them to the methylation and expression profiles of LMS patient samples (GSE68312). We focused on the genes that have decreased expression and are associated with increased methylation of the promoter CpG island regions in the patient LMS samples. In conclusion, treatment of SK-UT1 cell line with guadecitabine resulted in decrease of methylation of a subset of promoter CpG island regions that were differentially hypermethylated in LMS patient samples. Further studies are needed to explore the effect of differential methylation on gene expression in guadecitabine treated SK-UT1 cell line. Understanding the effect of DNMTi on LMS is needed to identify potential therapeutic applications targeting the epigenetic pathways. Funding supported by Astex Pharmaceuticals. Citation Format: Nesrin Hasan, Cynthia De Carvalho Fischer, Anup Sharma, Nita Ahuja. Hypermethylated genes in leiomyosarcoma can be targeted through guadecitabine treatment [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-015.
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