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Background <p>DOT1L, 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.</p> Methods <p>Estrogen 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.</p> Results <p>Treatment 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.</p> Conclusion <p>These findings suggest that the anti-breast cancer effect of DOT1L inhibition is mediated by multiple mechanisms, including activation of innate immune signaling.</p>

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DOT1L inhibition exerts the anti-tumor effect by activating interferon signaling in breast cancer cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月26日

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  • Ayano Yoshido,
  • Kazuya Ishiguro,
  • Hiroshi Kitajima,
  • Takeshi Niinuma,
  • Kohei Kumegawa,
  • Masaki Maezawa,
  • Tomohide Tsukahara,
  • Mutsumi Toyota,
  • Akira Yorozu,
  • Hajime Sasaki,
  • Eiichiro Yamamoto,
  • Masahiro Kai,
  • Masashi Idogawa,
  • Toshihiko Torigoe,
  • Hiroshi Nakase,
  • Reo Maruyama,
  • Hiromu Suzuki

摘要

Background

DOT1L, 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.

Methods

Estrogen 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.

Results

Treatment 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.

Conclusion

These findings suggest that the anti-breast cancer effect of DOT1L inhibition is mediated by multiple mechanisms, including activation of innate immune signaling.