2025年6月2日，丹娜法伯癌症研究所Kornelia Polyak研究小组在《自然—遗传学》杂志发表论文，报道了KDM4C抑制通过促进组织蛋白酶l介导的组蛋白H3切割来阻止基底乳腺癌的肿瘤生长。

在这里，该课题组人员描述了KDM4C组蛋白赖氨酸去甲基化酶在KDM4C扩增的基底乳腺癌中的独特作用，其中KDM4C抑制重塑染色质和转录组学格局，而不会实质性改变其典型底物，三甲基化组蛋白H3赖氨酸9 （H3K9me3）和赖氨酸36 （H3K36me3）。相反，KDM4C的丢失与组织蛋白酶L （CTSL）介导的组蛋白H3的蛋白水解裂解有关，导致谷氨酸-半胱氨酸连接酶表达下降和活性氧增加。KDM4C抑制后，GRHL2转录因子在赖氨酸453位点甲基化，触发CTSL组蛋白剪切活性，CTSL通过GRHL2转录因子募集到染色质上。CTSL的缺失挽救了KDM4C缺失介导的肿瘤抑制。他们的研究揭示了KDM4C连接细胞氧化还原调节和染色质重塑的功能。

据悉，基底乳腺癌是一种预后不良的亚型，需要更有效的治疗方法。

附：英文原文

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

Author: Li, Zheqi, Peluffo, Guillermo, Stevens, Laura E., Qiu, Xintao, Seehawer, Marco, Tawawalla, Amatullah, Huang, Xiao-Yun, Egri, Shawn B., Raval, Shaunak, McFadden, Maeve, DSantos, 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

Issue&Volume: 2025-06-02

Abstract: 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.

DOI: 10.1038/s41588-025-02197-z

Source: https://www.nature.com/articles/s41588-025-02197-z