Singh Shivendra, Abu-Zaid Ahmed, Lin Wenwei, Low Jonathan, Abdolvahabi Alireza, Jin Hongjian, Wu Qiong, Cooke Bailey, Fang Jie, Bowling John, Vaithiyalingam Sivaraja, Currier Duane, Yun Mi-Kyung, Fernando Dinesh M, Maier Julie, Tillman Heather, Bulsara Purva, Lu Zhaohua, Das Sourav, Shelat Anang, Li Zhenmei, Young Brandon, Lee Richard, Rankovic Zoran, Murphy Andrew J, White Stephen W, Davidoff Andrew M, Chen Taosheng, Yang Jun
Department of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USA.
Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
iScience. 2020 Dec 28;24(1):101996. doi: 10.1016/j.isci.2020.101996. eCollection 2021 Jan 22.
Histone lysine demethylases (KDMs) play critical roles in oncogenesis and therefore may be effective targets for anticancer therapy. Using a time-resolved fluorescence resonance energy transfer demethylation screen assay, in combination with multiple orthogonal validation approaches, we identified geldanamycin and its analog 17-DMAG as KDM inhibitors. In addition, we found that these Hsp90 inhibitors increase degradation of the alveolar rhabdomyosarcoma (aRMS) driver oncoprotein PAX3-FOXO1 and induce the repressive epigenetic mark H3K9me3 and H3K36me3 at genomic loci of PAX3-FOXO1 targets. We found that as monotherapy 17-DMAG significantly inhibits expression of PAX3-FOXO1 target genes and multiple oncogenic pathways, induces a muscle differentiation signature, delays tumor growth and extends survival in aRMS xenograft mouse models. The combination of 17-DMAG with conventional chemotherapy significantly enhances therapeutic efficacy, indicating that targeting KDM in combination with chemotherapy may serve as a therapeutic approach to PAX3-FOXO1-positive aRMS.
组蛋白赖氨酸去甲基化酶（KDMs）在肿瘤发生过程中发挥着关键作用，因此可能成为抗癌治疗的有效靶点。通过结合多种正交验证方法，利用时间分辨荧光共振能量转移去甲基化筛选试验，我们鉴定出格尔德霉素及其类似物17-DMAG为KDM抑制剂。此外，我们发现这些热休克蛋白90（Hsp90）抑制剂可增加肺泡横纹肌肉瘤（aRMS）驱动癌蛋白PAX3-FOXO1的降解，并在PAX3-FOXO1靶点的基因组位点诱导抑制性表观遗传标记H3K9me3和H3K36me3。我们发现，作为单一疗法，17-DMAG可显著抑制PAX3-FOXO1靶基因的表达和多种致癌途径，诱导肌肉分化特征，延缓肿瘤生长并延长aRMS异种移植小鼠模型的生存期。17-DMAG与传统化疗联合使用可显著提高治疗效果，表明靶向KDM与化疗联合使用可能是治疗PAX3-FOXO1阳性aRMS的一种治疗方法。
