ArticleClinical epigenetics2025
DOT1L inhibition exerts the anti-tumor effect by activating interferon signaling in breast cancer cells.
Article in Clinical epigenetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundDOT1L, a histone H3 lysine 79 (H3K79) methyltransferase, is a potential therapeutic target in various malignancies. In the present study, we aimed to clarify the anti-tumor effect of DOT1L inhibition in breast cancer.
methodsEstrogen receptor (ER)-positive/HER2-negative breast cancer cells (MCF7) and ER-negative/HER2-positive cells (SKBR3) were treated with a DOT1L inhibitor (SGC0946, EPZ-5676), after which colony formation assays, cell cycle assays, flow cytometry, gene expression microarray analysis, chromatin immunoprecipitation sequencing (ChIP-seq) and single-cell Assay for Transposase-Accessible Chromatin sequencing (scATAC-seq) were performed. Genetic ablation of STING was performed using the CRISPR/Cas9 system.
resultsTreatment with a DOT1L inhibitor suppressed proliferation and induced cell cycle arrest and apoptosis in both ER-positive/HER2-negative and ER-negative/HER2-positive cells. Transcriptome and epigenome analysis revealed that DOT1L inhibition activated transcription of a number of interferon (IFN)-related genes (IRGs) in breast cancer cells. We also found that DOT1L inhibition upregulated type I and type III IFNs as well as cell surface human leukocyte antigen (HLA) class I expression. Notably, DOT1L inhibition induced DNA damage and upregulated levels of cytoplasmic DNA in breast cancer cells. CRISPR/Cas9-mediated knockout of STING in breast cancer cells significantly suppressed the IFN signaling activated by DOT1L inhibition and attenuated the anti-tumor effect. Moreover, scATAC-seq analysis revealed that DOT1L inhibition suppressed expression of ERBB2 in HER2-positive breast cancer cells.
conclusionThese findings suggest that the anti-breast cancer effect of DOT1L inhibition is mediated by multiple mechanisms, including activation of innate immune signaling.
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