Li Zheqi, Peluffo Guillermo, Stevens Laura E, Qiu Xintao, Seehawer Marco, Tawawalla Amatullah, Huang Xiao-Yun, Egri Shawn B, Raval Shaunak, McFadden Maeve, D'Santos Clive S, Papachristou Eva, Kingston Natalie L, Nishida Jun, Evans Kyle E, Seo Ji-Heui, Clement Kendell, Temko Daniel, Ekram Muhammad, Li Rong, Rees Matthew G, Ronan Melissa M, Roth Jennifer A, Simeonov Anton, Kales Stephen C, Rai Ganesha, Lal-Nag Madhu, Maloney David J, Jadhav Ajit, Michor Franziska, Meissner Alex, Balko Justin M, Carroll Jason S, Freedman Matthew L, Jaffe Jacob D, Papanastasiou Malvina, Long Henry W, Polyak Kornelia
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Nat Genet. 2025 Jun 2. doi: 10.1038/s41588-025-02197-z.
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.
基底样乳腺癌是一种预后较差的亚型，需要更有效的治疗方法。在此，我们描述了KDM4C组蛋白赖氨酸去甲基化酶在KDM4C扩增的基底样乳腺癌中的独特作用，在这种癌症中，KDM4C抑制可重塑染色质和转录组景观，而其经典底物三甲基化组蛋白H3赖氨酸9（H3K9me3）和赖氨酸36（H3K36me3）没有实质性改变。相反，KDM4C缺失会导致组织蛋白酶L（CTSL）介导的组蛋白H3的蛋白水解切割，导致谷氨酸-半胱氨酸连接酶表达降低和活性氧增加。KDM4C抑制后，颗粒头样2（GRHL2）转录因子在赖氨酸453处发生甲基化，从而将CTSL招募至染色质，触发CTSL的组蛋白剪切活性。敲除CTSL可挽救KDM4缺失介导的肿瘤抑制作用。我们的研究揭示了KDM4C在连接细胞氧化还原调节和染色质重塑方面的功能。
