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.

基底乳腺癌是一种预后不良的亚型，需要更有效的治疗方法。在这里，我们描述了 KDM4C 组蛋白赖氨酸去甲基化酶在 KDM4C 扩增的基础乳腺癌中的独特作用，其中 KDM4C 抑制重塑染色质和转录组景观，而没有实质性改变其经典底物，三甲基化组蛋白 H3 赖氨酸 9 （H3K9me3） 和赖氨酸 36 （H3K36me3）。相反，KDM4C 缺失会导致组织蛋白酶 L （CTSL） 介导的组蛋白 H3 的蛋白水解裂解，导致谷氨酸-半胱氨酸连接酶表达降低和活性氧增加。CTSL 被粒状头样 2 （GRHL2） 转录因子募集到染色质中，该转录因子在 KDM4C 抑制后在赖氨酸 453 位点甲基化，触发 CTSL 组蛋白剪切活性。CTSL 缺失挽救了 KDM4 缺失介导的肿瘤抑制。我们的研究揭示了 KDM4C 连接细胞氧化还原调节和染色质重塑的功能。