Cellular senescence restrains the expansion of neoplastic cells through several layers of regulation, including epigenetic decoration of chromatin structure and functional modulation of bioactive components. Here we report that expression of the histone H3-specific demethylase KDM4 is upregulated in human stromal cells upon cellular senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation are correlated with adverse survival of cancer patients post-chemotherapy. Global chromatin accessibility mapping via ATAC-seq and expression profiling through RNA-seq reveal extensive reorganization of chromosomes and spatiotemporal reprogramming of the transcriptomic landscape, events responsible for development of the senescence-associated secretory phenotype (SASP). Selectively targeting KDM4 dampens the SASP of senescent stromal cells and enhances the apoptotic index of cancer cells in the treatment-damaged tumor microenvironment (TME), together prolonging overall survival of experimental animals. Our study supports the dynamic change of H3K9/H3K36 methylation marks during cellular senescence, identifies an unusually permissive chromatin state, unmasks KDM4 as a key modulator of the SASP, and presents a novel therapeutic avenue to manipulate cellular senescence and curtail age-related pathologies.

中文翻译：

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KDM4协调衰老细胞的表观基因组重塑并增强衰老相关的分泌表型。

细胞衰老通过几层调节，包括染色质结构的表观遗传修饰和生物活性成分的功能调节，来抑制肿瘤细胞的扩增。在这里我们报告说，细胞衰老后，人类基质细胞中组蛋白H3特异性脱甲基酶KDM4的表达上调。在临床肿瘤学中，KDM4上调和H3K9 / H3K36甲基化水平降低与癌症患者化疗后的不良生存相关。通过ATAC-seq进行的全球染色质可及性定位以及通过RNA-seq进行的表达谱分析揭示了染色体的广泛重组和转录组态势的时空重编程，这些事件是与衰老相关的分泌表型（SASP）发展的原因。选择性靶向KDM4可以抑制衰老的基质细胞的SASP并增强治疗受损的肿瘤微环境（TME）中癌细胞的凋亡指数，从而延长实验动物的整体存活期。我们的研究支持H3K9 / H3K36甲基化标记在细胞衰老过程中的动态变化，识别出异常允许的染色质状态，揭示KDM4作为SASP的关键调节剂，并提供了一种新的治疗途径来操纵细胞衰老和减少与年龄相关的病理。