Abstract
Abstract Cancer stem cells (CSCs) are a specific population of cancer cells that are responsible for tumor initiation, chemoresistance, and metastasis. Previously, our lab has demonstrated ovarian cancer cells with high aldehyde dehydrogenase (ALDH) activities have multiple stem cell-like characteristics, including self-renewal, high clonogenicity, and chemoresistance. Here we identify that H3K79 methyltransferase DOT1L (disruptor of telomeric silencing-1-like) is a critical factor in self-renewal and tumor initiation capabilities of ovarian cancer stem cells (OCSCs). Firstly, we found that DOT1L have higher expression in ALDH(+)/CD133(+) OCSCs compared to double negative cells. Ovarian cancer cells with DOT1L-knockdown have reduced CSC fractions in flow cytometry analysis. Besides, knockdown of DOT1L expression impairs clonogenicity characteristics of CSCs, according to in vitro colony-forming assay and spheroid formation assay results. In order to effectively inhibit the enzymatic activity of DOT1L, we applied specific DOT1L inhibitor (DOT1Li) EPZ5676 to specifically target OCSCs and confirmed that the treatment of DOT1Li was able to block H3K79 methylation in ovarian cancer cells, and effectively represses the expression of stemness-associated transcriptional factors. Results from RNA-seq analysis and gene set enrichment assay have indicated that multiple stem-related pathways are repressed in DOT1Li-treated OCSCs. Furthermore, DOT1Li treatment not only shows inhibitory effects on colony forming in vitro but also delays tumor initiation in vivo compared to control treatment, which validates the effects of DOT1Li on CSCs inhibition. Based on our result, we infer that DOT1L is critical for self-renewal and tumor initiation abilities in ovarian cancer stem cells, and DOT1L inhibition by specific inhibitor provides a potential therapeutic strategy to target CSCs in ovarian cancer treatment. Citation Format: Yaqi Zhang, Yinu Wang, Guangyuan Zhao, Daniela Matei. Targeting ovarian cancer stem cell by Dot1L inhibition [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A80.
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