Walters Zoë S, Aladowicz Ewa, Villarejo-Balcells Barbara, Nugent Gary, Selfe Joanna L, Eve Paul, Blagg Julian, Rossanese Olivia, Shipley Janet
Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, London SM2 5NG, UK.
Cancer Sciences, Faculty of Medicine, Southampton General Hospital, Southampton SO16 6YD, UK.
Cancers (Basel). 2021 Apr 6;13(7):1734. doi: 10.3390/cancers13071734.
Histone demethylases are epigenetic modulators that play key roles in regulating gene expression related to many critical cellular functions and are emerging as promising therapeutic targets in a number of tumor types. We previously identified histone demethylase family members as overexpressed in the pediatric sarcoma, rhabdomyosarcoma. Here we show high sensitivity of rhabdomyosarcoma cells to a pan-histone demethylase inhibitor, JIB-04 and identify a key role for the histone demethylase KDM4B in rhabdomyosarcoma cell growth through an RNAi-screening approach. Decreasing KDM4B levels affected cell cycle progression and transcription of G1/S and G2/M checkpoint genes including and , which are bound by KDM4B in their promoter regions. However, after sustained knockdown of KDM4B, rhabdomyosarcoma cell growth recovered. We show that this can be attributed to acquired molecular compensation via recruitment of KDM4A to the promoter regions of and that are otherwise bound by KDM4B. Furthermore, upfront silencing of both KDM4B and KDM4A led to RMS cell apoptosis, not seen by reducing either alone. To circumvent compensation and elicit stronger therapeutic responses, our study supports targeting histone demethylase sub-family proteins through selective poly-pharmacology as a therapeutic approach.
组蛋白去甲基化酶是表观遗传调节剂，在调节与许多关键细胞功能相关的基因表达中起关键作用，并且正在成为多种肿瘤类型中有前景的治疗靶点。我们之前发现组蛋白去甲基化酶家族成员在小儿肉瘤——横纹肌肉瘤中过表达。在此我们展示了横纹肌肉瘤细胞对一种泛组蛋白去甲基化酶抑制剂JIB-04具有高敏感性，并通过RNA干扰筛选方法确定了组蛋白去甲基化酶KDM4B在横纹肌肉瘤细胞生长中的关键作用。降低KDM4B水平影响细胞周期进程以及G1/S和G2/M检查点基因的转录，包括 和 ，这些基因在其启动子区域与KDM4B结合。然而，在持续敲低KDM4B后，横纹肌肉瘤细胞生长恢复。我们表明这可归因于通过将KDM4A招募到原本由KDM4B结合的 和 的启动子区域而获得的分子补偿。此外，预先沉默KDM4B和KDM4A均导致横纹肌肉瘤细胞凋亡，单独降低其中任何一个则未观察到这种现象。为了规避补偿并引发更强的治疗反应，我们的研究支持通过选择性多药理学靶向组蛋白去甲基化酶亚家族蛋白作为一种治疗方法。
