Context-Specific Effects of TGF-β/SMAD3 in Cancer Are Modulated by the Epigenome.
Context-Specific Effects of TGF-β/SMAD3 in Cancer Are Modulated by the Epigenome.
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DOI：
10.1016/j.celrep.2015.11.040
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发表时间：
2015-12-22
期刊：
影响因子：
8.8
通讯作者：
Caldas C
中科院分区：
文献类型：
--
作者：
Tufegdzic Vidakovic A;Rueda OM;Vervoort SJ;Sati Batra A;Goldgraben MA;Uribe-Lewis S;Greenwood W;Coffer PJ;Bruna A;Caldas C
转化生长因子β (TGF-β)信号通路对癌细胞发挥相反的作用，既可以作为肿瘤启动子，也可以作为肿瘤抑制因子。在这里，我们表明这些相反的作用是SMAD3 （TGF-β信号的下游效应物）和乳腺肿瘤启动细胞（BTICs）的不同表观基因组之间协同作用的结果。TGF-β的这些作用与不同的基因表达程序有关，但在btic促进和btic抑制的背景下，基因组SMAD3的结合模式是高度相似的。我们的数据显示，细胞类型特异性的DNA模式和组蛋白修饰通过决定基因对TGF-β/SMAD3调控的可及性提供了一个调节层。LBH就是这样一种环境特异性靶基因，根据其DNA甲基化状态进行调控，对于TGF-β依赖性促进btic至关重要。总的来说，这些结果揭示了表观基因组在塑造TGF-β在癌症中的环境特异性作用方面起着核心作用，但以前被忽视了。TGF-β在不同乳腺肿瘤启动细胞（breast-tumor- initiation cell， BTIC）中具有相反的作用，SMAD3在BTIC中具有相似的结合模式，对TGF-β具有相反的应答。BTIC类型特异性的表观基因组是TGF-β/SMAD3调控的主要基因。LBH是TGF-β的类型特异性靶点，是TGF-β促进BTIC作用的关键。TGF-β通路通过SMAD转录因子进行转录调控，调节细胞环境特异性表型。Tufegdzic Vidakovic等人的研究表明，在乳腺肿瘤启动细胞（BTICs）中，类型特异性DNA和组蛋白修饰有助于确定对TGF-β的反应是促癌还是抑瘤。这些景观既协同作用，又独立于细胞类型特异性SMAD3结合TGF-β靶基因，通过TGF-β/SMAD3调节环境特异性转录调节。
The transforming growth factor beta (TGF-β) signaling pathway exerts opposing effects on cancer cells, acting as either a tumor promoter or a tumor suppressor. Here, we show that these opposing effects are a result of the synergy between SMAD3, a downstream effector of TGF-β signaling, and the distinct epigenomes of breast-tumor-initiating cells (BTICs). These effects of TGF-β are associated with distinct gene expression programs, but genomic SMAD3 binding patterns are highly similar in the BTIC-promoting and BTIC-suppressing contexts. Our data show cell-type-specific patterns of DNA and histone modifications provide a modulatory layer by determining accessibility of genes to regulation by TGF-β/SMAD3. LBH, one such context-specific target gene, is regulated according to its DNA methylation status and is crucial for TGF-β-dependent promotion of BTICs. Overall, these results reveal that the epigenome plays a central and previously overlooked role in shaping the context-specific effects of TGF-β in cancer. TGF-β has opposing effects in different breast-tumor-initiating cell (BTIC) types Genomic SMAD3 binding patterns are similar in BTICs with opposing responses to TGF-β BTIC type-specific epigenomes prime genes for regulation by TGF-β/SMAD3 LBH, a type-specific TGF-β target, is essential for BTIC-promoting effects of TGF-β The TGF-β pathway uses transcriptional regulation through SMAD transcription factors to modulate cell-context-specific phenotypes. Tufegdzic Vidakovic et al. show that in breast-tumor-initiating cells (BTICs), type-specific DNA and histone modifications help determine whether the response to TGF-β is pro-oncogenic or tumor suppressive. These landscapes act both in synergy and independently of cell-type-specific SMAD3 binding to TGF-β target genes to modulate context-specific transcriptional regulation by TGF-β/SMAD3.