MEK inhibition induces MYOG and remodels super-enhancers in RAS-driven rhabdomyosarcoma.
MEK inhibition induces MYOG and remodels super-enhancers in RAS-driven rhabdomyosarcoma.
复制标题
DOI：
10.1126/scitranslmed.aan4470
复制
发表时间：
2018-07-04
影响因子：
17.1
通讯作者：
Khan J
中科院分区：
文献类型：
--
作者：
Yohe ME;Gryder BE;Shern JF;Song YK;Chou HC;Sindiri S;Mendoza A;Patidar R;Zhang X;Guha R;Butcher D;Isanogle KA;Robinson CM;Luo X;Chen JQ;Walton A;Awasthi P;Edmondson EF;Difilippantonio S;Wei JS;Zhao K;Ferrer M;Thomas CJ;Khan J
RAS亚型在许多类型的人类癌症中经常发生突变，包括PAX3/PAX7融合阴性横纹肌肉瘤。小儿RMS源于骨骼肌祖细胞不能正常分化。突变体RAS在这种分化阻断中的作用尚不完全清楚。我们证明了致癌RAS，通过RAF-MEK[丝裂原活化蛋白激酶（MAPK）激酶]-ERK（细胞外信号调节激酶）MAPK效应通路，通过抑制前分化肌源性转录因子MYOG的表达，抑制横纹肌肉瘤的肌源性分化。这种抑制是由erk2依赖性启动子介导的，MYOG位点上RNA聚合酶II的近端延迟。用机制定义抑制剂库进行小分子筛选表明，ras驱动的RMS易受MEK抑制。用曲美替尼抑制MEK可导致MYOG启动子处ERK2的缺失，并释放MYOG表达的转录停滞。MYOG随后打开染色质并在晚期肌源性分化所需的基因上建立超级增强子。此外，在异种移植模型中，曲美替尼与IGF1R抑制剂联合使用可有效降低横纹肌肉瘤细胞活力并减缓肿瘤生长。因此，这种组合代表了ras突变横纹肌肉瘤的潜在治疗方法。
The RAS isoforms are frequently mutated in many types of human cancers, including PAX3/PAX7 fusion-negative rhabdomyosarcoma. Pediatric RMS arises from skeletal muscle progenitor cells that have failed to differentiate normally. The role of mutant RAS in this differentiation blockade is incompletely understood. We demonstrate that oncogenic RAS, acting through the RAF–MEK [mitogen-activated protein kinase (MAPK) kinase]–ERK (extracellular signal–regulated kinase) MAPK effector pathway, inhibits myogenic differentiation in rhabdomyosarcoma by repressing the expression of the prodifferentiation myogenic transcription factor, MYOG. This repression is mediated by ERK2-dependent promoter-proximal stalling of RNA polymerase II at the MYOG locus. Small-molecule screening with a library of mechanistically defined inhibitors showed that RAS-driven RMS is vulnerable to MEK inhibition. MEK inhibition with trametinib leads to the loss of ERK2 at the MYOG promoter and releases the transcriptional stalling of MYOG expression. MYOG subsequently opens chromatin and establishes super-enhancers at genes required for late myogenic differentiation. Furthermore, trametinib, in combination with an inhibitor of IGF1R, potently decreases rhabdomyosarcoma cell viability and slows tumor growth in xenograft models. Therefore, this combination represents a potential therapeutic for RAS-mutated rhabdomyosarcoma.
登录
查看更多内容
影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
14.8
作者：
Chaikuad A;Tacconi EM;Zimmer J;Liang Y;Gray NS;Tarsounas M;Knapp S
通讯作者：
Knapp S
影响因子：
8
作者：
Dorman, CM;Johnson, SE
通讯作者：
Johnson, SE
弥漫性大 B 细胞淋巴瘤中超级增强子相关依赖性的发现和表征。
影响因子：
50.3
作者：
Chapuy B;McKeown MR;Lin CY;Monti S;Roemer MG;Qi J;Rahl PB;Sun HH;Yeda KT;Doench JG;Reichert E;Kung AL;Rodig SJ;Young RA;Shipp MA;Bradner JE
通讯作者：
Bradner JE
影响因子：
16
作者：
Goeke, Jonathan;Chan, Yun-Shen;Ng, Huck-Hui
通讯作者：
Ng, Huck-Hui