DOT1 L Regulates Ovarian Cancer Stem Cells by Activating β-catenin Signaling

作者：Yaqi Zhang, Yinu Wang, Andres Valdivia, Hao Huang, Daniela Matei · 发表于：Molecular Cancer Research · 年份：2022 · DOI：10.1158/1541-7786.mcr-22-0418 · 被引用次数：12 · 研究领域：Cancer Cells and Metastasis、Epigenetics and DNA Methylation、Cancer, Hypoxia, and Metabolism

Cancer stem cells (CSC) represent a population of cancer cells responsible for tumor initiation, chemoresistance, and metastasis. Here, we identified the H3K79 methyltransferase disruptor of telomeric silencing-1-like (DOT1L) as a critical regulator of self-renewal and tumor initiation in ovarian CSCs. DOT1 L was upregulated in ovarian CSCs versus non-CSCs. shRNA-mediated DOT1 L knockdown decreased the aldehyde dehydrogenase (ALDH)+ cell population, impaired the tumor initiation capacity (TIC) of ovarian CSCs, and blocked the expression of stemness-associated genes. Inhibition of DOT1L's methyltransferase activity by the small-molecule inhibitor (DOT1Li) EPZ-5676 also effectively targeted ovarian CSCs. Integrated RNA-sequencing analyses of ovarian cancer cells in which DOT1 L was knocked down versus control cells and of ovarian CSCs versus non-CSCs, identified Wnt signaling as a shared pathway deregulated in both CSCs and in DOT1L-deficient ovarian cancer cells. β-catenin, a key transcription factor regulated by Wnt, was downregulated in ovarian cancer cells in which DOT1 L was knocked down and upregulated in DOT1 L overexpressing ovarian cancer cells. Chromatin immunoprecipitation (ChIP) revealed enrichment of the H3K79Me3 mark at the β-catenin promoter, suggesting that its transcription is regulated by DOT1L. Our results suggest that DOT1 L is critical for the self-renewal and TIC of ovarian CSCs by regulating β-catenin signaling. Targeting DOT1 L in ovarian cancer could be...