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<p>Basal breast cancer is a subtype with a poor prognosis in need of more effective therapeutic approaches. Here we describe a unique role for the KDM4C histone lysine demethylase in <i>KDM4C</i>-amplified basal breast cancers, where KDM4C inhibition reshapes chromatin and transcriptomic landscapes without substantial alterations of its canonical substrates, trimethylated histone H3 lysine 9 (H3K9me3) and lysine 36 (H3K36me3). Rather, KDM4C loss causes proteolytic cleavage of histone H3 mediated by cathepsin L (CTSL), resulting in decreased glutamate–cysteine ligase expression and increased reactive oxygen species. CTSL is recruited to the chromatin by the grainyhead-like 2 (GRHL2) transcription factor that is methylated at lysine 453 following KDM4C inhibition, triggering CTSL histone clipping activity. Deletion of CTSL rescued KDM4-loss-mediated tumor suppression. Our study reveals a function for KDM4C that connects cellular redox regulation and chromatin remodeling.</p>

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KDM4C inhibition blocks tumor growth in basal breast cancer by promoting cathepsin L-mediated histone H3 cleavage

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月2日

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  • Zheqi Li,
  • Guillermo Peluffo,
  • Laura E. Stevens,
  • Xintao Qiu,
  • Marco Seehawer,
  • Amatullah Tawawalla,
  • Xiao-Yun Huang,
  • Shawn B. Egri,
  • Shaunak Raval,
  • Maeve McFadden,
  • Clive S. D’Santos,
  • Eva Papachristou,
  • Natalie L. Kingston,
  • Jun Nishida,
  • Kyle E. Evans,
  • Ji-Heui Seo,
  • Kendell Clement,
  • Daniel Temko,
  • Muhammad Ekram,
  • Rong Li,
  • Matthew G. Rees,
  • Melissa M. Ronan,
  • Jennifer A. Roth,
  • Anton Simeonov,
  • Stephen C. Kales,
  • Ganesha Rai,
  • Madhu Lal-Nag,
  • David J. Maloney,
  • Ajit Jadhav,
  • Franziska Michor,
  • Alex Meissner,
  • Justin M. Balko,
  • Jason S. Carroll,
  • Matthew L. Freedman,
  • Jacob D. Jaffe,
  • Malvina Papanastasiou,
  • Henry W. Long,
  • Kornelia Polyak

摘要

Basal breast cancer is a subtype with a poor prognosis in need of more effective therapeutic approaches. Here we describe a unique role for the KDM4C histone lysine demethylase in KDM4C-amplified basal breast cancers, where KDM4C inhibition reshapes chromatin and transcriptomic landscapes without substantial alterations of its canonical substrates, trimethylated histone H3 lysine 9 (H3K9me3) and lysine 36 (H3K36me3). Rather, KDM4C loss causes proteolytic cleavage of histone H3 mediated by cathepsin L (CTSL), resulting in decreased glutamate–cysteine ligase expression and increased reactive oxygen species. CTSL is recruited to the chromatin by the grainyhead-like 2 (GRHL2) transcription factor that is methylated at lysine 453 following KDM4C inhibition, triggering CTSL histone clipping activity. Deletion of CTSL rescued KDM4-loss-mediated tumor suppression. Our study reveals a function for KDM4C that connects cellular redox regulation and chromatin remodeling.