17-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma.
17-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma.
复制标题
DOI：
10.1016/j.isci.2020.101996
复制
发表时间：
2021-01-22
期刊：
影响因子：
5.8
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Singh S;Abu-Zaid A;Lin W;Low J;Abdolvahabi A;Jin H;Wu Q;Cooke B;Fang J;Bowling J;Vaithiyalingam S;Currier D;Yun MK;Fernando DM;Maier J;Tillman H;Bulsara P;Lu Z;Das S;Shelat A;Li Z;Young B;Lee R;Rankovic Z;Murphy AJ;White SW;Davidoff AM;Chen T;Yang J
组蛋白赖氨酸去甲基化酶（kdm）在肿瘤发生中起关键作用，因此可能是抗癌治疗的有效靶点。利用时间分辨荧光共振能量转移去甲基化筛选试验，结合多重正交验证方法，我们确定格尔达霉素及其类似物17-DMAG为KDM抑制剂。此外，我们发现这些Hsp90抑制剂增加了肺泡横纹肌肉瘤（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表观遗传标记H3K9me3和H3K36me3。我们发现单药17-DMAG显著抑制PAX3-FOXO1靶基因和多种致癌途径的表达，诱导肌肉分化特征，延缓肿瘤生长，延长aRMS异种移植小鼠模型的生存期。17-DMAG联合常规化疗可显著提高治疗效果，提示联合化疗靶向KDM可作为治疗pax3 - fox01阳性aRMS的一种途径。格尔达霉素/17-DMAG作为组蛋白赖氨酸去甲基化酶抑制剂的鉴定格尔达霉素/17-DMAG导致PAX3-FOXO1降解，Hsp90客户端格尔达霉素/17-DMAG诱导表观遗传变化并靶向PAX3-FOXO1通路17-DMAG单独或联合化疗对PAX3-FOXO1异种移植物显示药效；癌症;组学
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. Identification of geldanamycin/17-DMAG as histone lysine demethylase inhibitors Geldanamycin/17-DMAG causes degradation of PAX3-FOXO1, an Hsp90 client Geldanamycin/17-DMAG induces epigenetic changes and targets PAX3-FOXO1 pathway 17-DMAG alone or combined with chemotherapy show potency to PAX3-FOXO1 xenografts Molecular Biology; Cancer; Omics
登录
查看更多内容
影响因子：
3.2
作者：
Lock, Richard B.;Carol, Hernan;Maris, John M.;Kang, Min H.;Reynolds, C. Patrick;Kolb, E. Anders;Gorlick, Richard;Keir, Stephen T.;Billups, Catherine A.;Kurmasheva, Raushan T.;Houghton, Peter J.;Smith, Malcolm A.
通讯作者：
Smith, Malcolm A.
影响因子：
10.3
作者：
Asgharzadeh, Shahab;Pique-Regi, Roger;Seeger, Robert C.
通讯作者：
Seeger, Robert C.
影响因子：
--
作者：
Duan L;Rai G;Roggero C;Zhang QJ;Wei Q;Ma SH;Zhou Y;Santoyo J;Martinez ED;Xiao G;Raj GV;Jadhav A;Simeonov A;Maloney DJ;Rizo J;Hsieh JT;Liu ZP
通讯作者：
Liu ZP
影响因子：
16
作者：
Das, Partha Pratim;Shao, Zhen;Beyaz, Semir;Apostolou, Eftychia;Pinello, Luca;De Los Angeles, Alejandro;O'Brien, Kassandra;Atsma, Jennifer Marino;Fujiwara, Yuko;Minh Nguyen;Ljuboja, Damir;Guo, Guoji;Woo, Andrew;Yuan, Guo-Cheng;Onder, Tamer;Daley, George;Hochedlinger, Konrad;Kim, Jonghwan;Orkin, Stuart H.
通讯作者：
Orkin, Stuart H.
影响因子：
11.2
作者：
Cao, Liang;Yu, Yunkai;Meltzer, Paul S.
通讯作者：
Meltzer, Paul S.