Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation.
Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation.
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DOI：
10.1084/jem.20170724
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发表时间：
2017-08-07
期刊：
影响因子：
--
通讯作者：
Dotto GP
中科院分区：
文献类型：
--
作者：
Kim DE;Procopio MG;Ghosh S;Jo SH;Goruppi S;Magliozzi F;Bordignon P;Neel V;Angelino P;Dotto GP
癌症相关成纤维细胞（CAF）的活化促进肿瘤发生。Kim等人表明，ATF 3和CSL通过长距离染色质控制在CAF激活的负调控中会聚。溴结构域和末端外（BET）抑制剂抵消了CAF活化和癌症基质细胞扩增中ATF 3和CSL损失的作用。癌症相关成纤维细胞（CAF）对于肿瘤的发生和促进是重要的。CSL是一种转录抑制因子和Notch介导因子，抑制CAF激活。与CSL一样，ATF 3是一种应激反应性转录抑制因子，在皮肤癌基质细胞中下调，并且Atf 3敲除小鼠发展具有增强的CAF激活的侵袭性化学诱导的皮肤肿瘤。即使在低基础水平下，ATF 3在全局染色质控制中也与CSL收敛，与距离靶基因很远的少数基因组位点结合。与这种调控模式一致，IL 6上游2 Mb的一个这样的位点的缺失诱导基因的表达。观察到的变化具有翻译意义，因为溴结构域和末端外（BET）抑制剂使活化的染色质与基础转录分离，抵消ATF 3或CSL损失对整体基因表达的影响，并在鳞状细胞癌-基质细胞扩增的体内模型中抑制CAF肿瘤促进特性。因此，在CAF活化的阴性对照中，ATF 3与CSL收敛，表观遗传变化适合于癌症和基质集中的干预。
Activation of cancer-associated fibroblasts (CAFs) promotes tumorigenesis. Kim et al. show that ATF3 and CSL converge in negative regulation of CAF activation through long-distance chromatin control. Bromodomain and extra-terminal (BET) inhibitors counteract the effects of ATF3 and CSL loss in CAF activation and cancer–stromal cell expansion. Cancer-associated fibroblasts (CAFs) are important for tumor initiation and promotion. CSL, a transcriptional repressor and Notch mediator, suppresses CAF activation. Like CSL, ATF3, a stress-responsive transcriptional repressor, is down-modulated in skin cancer stromal cells, and Atf3 knockout mice develop aggressive chemically induced skin tumors with enhanced CAF activation. Even at low basal levels, ATF3 converges with CSL in global chromatin control, binding to few genomic sites at a large distance from target genes. Consistent with this mode of regulation, deletion of one such site 2 Mb upstream of IL6 induces expression of the gene. Observed changes are of translational significance, as bromodomain and extra-terminal (BET) inhibitors, unlinking activated chromatin from basic transcription, counteract the effects of ATF3 or CSL loss on global gene expression and suppress CAF tumor-promoting properties in an in vivo model of squamous cancer–stromal cell expansion. Thus, ATF3 converges with CSL in negative control of CAF activation with epigenetic changes amenable to cancer- and stroma-focused intervention.
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影响因子：
64.5
作者：
Hu B;Castillo E;Harewood L;Ostano P;Reymond A;Dummer R;Raffoul W;Hoetzenecker W;Hofbauer GF;Dotto GP
通讯作者：
Dotto GP
影响因子：
8
作者：
Hinata, K;Gervin, AM;Khavari, PA
通讯作者：
Khavari, PA
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
19
作者：
Goruppi, Sandro;Dotto, G. Paolo
通讯作者：
Dotto, G. Paolo
影响因子：
21.3
作者：
Procopio MG;Laszlo C;Al Labban D;Kim DE;Bordignon P;Jo SH;Goruppi S;Menietti E;Ostano P;Ala U;Provero P;Hoetzenecker W;Neel V;Kilarski WW;Swartz MA;Brisken C;Lefort K;Dotto GP
通讯作者：
Dotto GP