Sin3a acts through a multi-gene module to regulate invasion in Drosophila and human tumors.
Sin3a acts through a multi-gene module to regulate invasion in Drosophila and human tumors.
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DOI：
10.1038/onc.2012.326
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发表时间：
2013-06-27
期刊：
影响因子：
8
通讯作者：
Cagan, R. L.
中科院分区：
文献类型：
--
作者：
Das, T. K.;Sangodkar, J.;Negre, N.;Narla, G.;Cagan, R. L.
染色质重塑蛋白调节细胞内稳态的多个方面，使它们成为转化细胞中调节不当的理想对象。在这里，我们探索Sin3A，与肿瘤发生相关的Sin3蛋白家族的成员，被认为通过组蛋白脱乙酰酶(HDAC)的作用来调节基因的表达。在多发性内分泌肿瘤2型的果蝇模型中，我们发现果蝇Sin3a是致癌Ret受体的重要介导物。降低果蝇Sin3a的活性会导致转移样行为，并且在DIAP1存在的情况下，会导致远离起始点的继发性肿瘤。基因和芯片序列分析确定了以前未描述的Sin3a靶标，包括与细胞运动和肌动蛋白动力学有关的基因，以及包括Src、JNK和Rho在内的信号通路。一个关键的SIN3a致癌靶点，PP1B，调节β-连环蛋白/Armadillo的稳定性：其结果是在苍蝇和哺乳动物的癌细胞中都反对T细胞因子(Tcf)的功能和Wg/Wnt通路信号。降低SIN3A显著增加A549人肺腺癌细胞的侵袭行为。我们发现Sin3A在各种人类肿瘤中表达下调，而Src、JNK、RhoA和PP1B/β-catenin的调节方式与我们的果蝇模型相似。我们的数据表明，Sin3A通过调节与细胞侵袭有关的基因模块来影响肿瘤发生的特定步骤。肿瘤的进展可能通常依赖于广泛转录调节因子控制下的“侵袭模块”。
Chromatin remodeling proteins regulate multiple aspects of cell homeostasis, making them ideal candidates for misregulation in transformed cells. Here, we explore Sin3A, a member of the Sin3 family of proteins linked to tumorigenesis that are thought to regulate gene expression through their role as histone deacetylases (HDACs). We identified Drosophila Sin3a as an important mediator of oncogenic Ret receptor in a fly model of Multiple Endocrine Neoplasia Type 2. Reducing Drosophila Sin3a activity led to metastasis-like behavior and, in the presence of Diap1, secondary tumors distant from the site of origin. Genetic and Chip-Seq analyses identified previously undescribed Sin3a targets including genes involved in cell motility and actin dynamics, as well as signaling pathways including Src, Jnk and Rho. A key Sin3a oncogenic target, PP1B, regulates stability of β-Catenin/Armadillo: the outcome is to oppose T-cell factor (TCF) function and Wg/Wnt pathway signaling in both fly and mammalian cancer cells. Reducing Sin3A strongly increased the invasive behavior of A549 human lung adenocarcinoma cells. We show that Sin3A is downregulated in a variety of human tumors and that Src, JNK, RhoA and PP1B/β-Catenin are regulated in a manner analogous to our Drosophila models. Our data suggest that Sin3A influences a specific step of tumorigenesis by regulating a module of genes involved in cell invasion. Tumor progression may commonly rely on such ‘modules of invasion’ under the control of broad transcriptional regulators.
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影响因子：
11.2
作者：
Castellone MD;De Falco V;Rao DM;Bellelli R;Muthu M;Basolo F;Fusco A;Gutkind JS;Santoro M
通讯作者：
Santoro M
影响因子：
64.5
作者：
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通讯作者：
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影响因子：
5.3
作者：
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通讯作者：
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影响因子：
3.3
作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
Steinkuhler, Christian