TWIST2-mediated chromatin remodeling promotes fusion-negative rhabdomyosarcoma.
TWIST2-mediated chromatin remodeling promotes fusion-negative rhabdomyosarcoma.
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TWIST2介导的染色质重塑促进融合阴性横纹肌肉瘤
DOI：
10.1126/sciadv.ade8184
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发表时间：
2023-04-28
期刊：
影响因子：
13.6
通讯作者：
Liu, Ning
中科院分区：
文献类型：
--
作者：
Shah, Akansha M.;Guo, Lei;Morales, Maria Gabriela;Jaichander, Priscilla;Chen, Kenian;Huang, Huocong;Hernandez, Karla Cano;Xu, Lin;Bassel-Duby, Rhonda;Olson, Eric N.;Liu, Ning
横纹肌肉瘤（RMS）是一种常见的软组织肉瘤在儿童，类似于发展中的骨骼肌。与正常肌细胞不同，RMS细胞不能分化，尽管表达成肌决定蛋白MYOD。TWIST 2转录因子在融合阴性RMS（FN-RMS）中经常过表达。TWIST 2通过抑制成肌细胞中的MYOD活性来阻断分化，但其在FN-RMS发病机制中的作用尚不完全清楚。在这里，我们表明，敲低TWIST 2使FN-RMS细胞退出细胞周期，并进行终末肌生成。TWIST 2敲低还显著降低了FN-RMS小鼠异种移植模型中的肿瘤生长。从机制上讲，TWIST 2通过与染色质重塑物SMARCA 4和CHD 3相互作用来控制远端增强子处的H3 K27乙酰化，以激活生长相关靶基因并抑制肌生成相关靶基因。这些发现提供了对TWIST 2在维持FN-RMS的未分化和致瘤状态中的作用的见解，并强调了抑制TWIST 2调节通路以治疗FN-RMS的潜力。Twist 2控制促进融合阴性横纹肌肉瘤的基因调控程序。
Rhabdomyosarcoma (RMS) is a common soft tissue sarcoma in children that resembles developing skeletal muscle. Unlike normal muscle cells, RMS cells fail to differentiate despite expression of the myogenic determination protein MYOD. The TWIST2 transcription factor is frequently overexpressed in fusion-negative RMS (FN-RMS). TWIST2 blocks differentiation by inhibiting MYOD activity in myoblasts, but its role in FN-RMS pathogenesis is incompletely understood. Here, we show that knockdown of TWIST2 enables FN-RMS cells to exit the cell cycle and undergo terminal myogenesis. TWIST2 knockdown also substantially reduces tumor growth in a mouse xenograft model of FN-RMS. Mechanistically, TWIST2 controls H3K27 acetylation at distal enhancers by interacting with the chromatin remodelers SMARCA4 and CHD3 to activate growth-related target genes and repress myogenesis-related target genes. These findings provide insights into the role of TWIST2 in maintaining an undifferentiated and tumorigenic state of FN-RMS and highlight the potential of suppressing TWIST2-regulated pathways to treat FN-RMS. Twist2 controls a gene regulatory program that promotes fusion-negative rhabdomyosarcoma.
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