Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor.
Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor.
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米特拉霉素诱导横纹肌样肿瘤启动子重编程和分化
DOI：
10.15252/emmm.202012640
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发表时间：
2021-02-05
影响因子：
11.1
通讯作者：
Grohar PJ
中科院分区：
文献类型：
--
作者：
Chasse MH;Johnson BK;Boguslawski EA;Sorensen KM;Rosien JE;Kang MH;Reynolds CP;Heo L;Madaj ZB;Beddows I;Foxa GE;Kitchen-Goosen SM;Williams BO;Triche TJ Jr;Grohar PJ
横纹肌样瘤（RT）是一种儿科癌症，其特征是SMARCB 1（SWI/SNF染色质重塑复合物的亚基）失活。虽然这种缺失是已知的致癌驱动因素，但这些患者的有效治疗选择有限。在这里，我们使用细胞系组的无偏筛选来鉴定横纹肌样瘤对光辉霉素和第二代类似物EC 8042的敏感性增加。MMA和EC 8042的敏感性上级于传统的DNA损伤剂，并且与肿瘤的致病突变SMARCB 1缺失相关。光辉霉素阻断SMARCB 1缺陷SWI/SNF活性，并从染色质中置换复合物，导致H3 K27 me 3增加。这触发了染色质重塑和H3 K27 ac在chromHMM定义的启动子处的富集，以恢复细胞分化。这些作用发生在与DNA损伤无关的浓度下，并且不是由于整体染色质重塑或广泛的基因表达变化。重要的是，EC 8042的单次3天输注引起RT异种移植物的显著消退，重现了体外描述的H3 K27 me 3和细胞分化的增加，以完全治愈八只小鼠中的三只。EC 8042被鉴定为致癌SWI/SNF的抑制剂，并且是横纹肌样肿瘤的有希望的治疗候选物。阐明靶抑制的机制并用于优化化合物给药、表征相关生物标志物和治愈携带横纹肌样肿瘤异种移植物的小鼠。
Rhabdoid tumor (RT) is a pediatric cancer characterized by the inactivation of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. Although this deletion is the known oncogenic driver, there are limited effective therapeutic options for these patients. Here we use unbiased screening of cell line panels to identify a heightened sensitivity of rhabdoid tumor to mithramycin and the second‐generation analogue EC8042. The sensitivity of MMA and EC8042 was superior to traditional DNA damaging agents and linked to the causative mutation of the tumor, SMARCB1 deletion. Mithramycin blocks SMARCB1‐deficient SWI/SNF activity and displaces the complex from chromatin to cause an increase in H3K27me3. This triggers chromatin remodeling and enrichment of H3K27ac at chromHMM‐defined promoters to restore cellular differentiation. These effects occurred at concentrations not associated with DNA damage and were not due to global chromatin remodeling or widespread gene expression changes. Importantly, a single 3‐day infusion of EC8042 caused dramatic regressions of RT xenografts, recapitulated the increase in H3K27me3, and cellular differentiation described in vitro to completely cure three out of eight mice. EC8042 is identified as an inhibitor of oncogenic SWI/SNF and a promising therapeutic candidate for rhabdoid tumor. The mechanism of target inhibition is elucidated and used to optimize compound administration, characterize an associated biomarker, and cure mice bearing rhabdoid tumor xenografts.
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影响因子：
12.3
作者：
Fortin JP;Hansen KD
通讯作者：
Hansen KD
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10.5
作者：
Kadam, S;McAlpine, GS;Emerson, BM
通讯作者：
Emerson, BM
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作者：
Harlow, Matt L.;Maloney, Nichole;Grohar, Patrick J.
通讯作者：
Grohar, Patrick J.
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