The histone lysine demethylases KDM4A-C are involved in physiologic processes including stem cell identity and self-renewal during development, DNA-damage repair, and cell cycle progression. KDM4A-C are overexpressed and associated with malignant cell behavior in multiple human cancers and are therefore potential therapeutic targets. Given the role of KDM4A-C in development and cancer, we aimed to test the potent, selective KDM4A-C inhibitor QC6352 on oncogenic cells of renal embryonic lineage. The anaplastic Wilms tumor cell line WiT49 and the tumor-forming human embryonic kidney cell line HEK293 demonstrated low nanomolar QC6352 sensitivity. The cytostatic response to QC6352 in WiT49 and HEK293 cells was marked by induction of DNA damage, a DNA repair-associated protein checkpoint response, S-phase cell cycle arrest, profound reduction of ribosomal protein gene and rRNA transcription, and blockade of newly synthesized proteins. QC6352 caused reduction of KDM4A-C levels by a proteasome-associated mechanism. The cellular phenotype caused by QC6352 treatment of reduced migration, proliferation, tumor spheroid growth, DNA damage, and S-phase cell cycle arrest was most closely mirrored by knockdown of KDM4A as determined by siRNA knockdown of KDM4A-C. QC6352 sensitivity correlated with high basal levels of ribosomal gene transcription in over 900 human cancer cell lines. Targeting KDM4A may be of future therapeutic interest in oncogenic cells of embryonic renal lineage or cells with high basal expression of ribosomal protein genes.

中文翻译：

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对小分子抑制剂 QC6352 敏感的肾胚胎谱系致癌细胞表现出 KDM4 水平的耗尽和核糖体生物发生的破坏

组蛋白赖氨酸去甲基酶 KDM4A-C 参与生理过程，包括发育过程中的干细胞身份和自我更新、DNA 损伤修复和细胞周期进展。KDM4A-C 在多种人类癌症中过度表达并与恶性细胞行为相关，因此是潜在的治疗靶点。鉴于 KDM4A-C 在发育和癌症中的作用，我们旨在测试有效的选择性 KDM4A-C 抑制剂 QC6352 对肾胚胎谱系致癌细胞的作用。间变性肾母细胞瘤细胞系 WiT49 和肿瘤形成人胚胎肾细胞系 HEK293 表现出低纳摩尔级 QC6352 敏感性。WiT49 和 HEK293 细胞中对 QC6352 的细胞抑制反应的特点是诱导 DNA 损伤、DNA 修复相关蛋白检查点反应、S 期细胞周期停滞、核糖体蛋白基因和 rRNA 转录的显着减少以及新合成蛋白的阻断。QC6352 通过蛋白酶体相关机制导致 KDM4A-C 水平降低。由 QC6352 处理引起的迁移、增殖、肿瘤球体生长、DNA 损伤和 S 期细胞周期停滞减少的细胞表型与 KDM4A 的敲低最接近地反映，如通过 KDM4A-C 的 siRNA 敲低所确定的。QC6352 敏感性与 900 多种人类癌细胞系中核糖体基因转录的高基础水平相关。靶向 KDM4A 可能对胚胎肾谱系的致癌细胞或核糖体蛋白基因基础表达高的细胞具有未来的治疗意义。