The Transcriptional Regulators TAZ and YAP Direct Transforming Growth Factor β-induced Tumorigenic Phenotypes in Breast Cancer Cells
The Transcriptional Regulators TAZ and YAP Direct Transforming Growth Factor β-induced Tumorigenic Phenotypes in Breast Cancer Cells
复制标题
DOI：
10.1074/jbc.m113.529115
复制
发表时间：
2014-05-09
影响因子：
4.8
通讯作者：
Varelas, Xaralabos
中科院分区：
文献类型：
--
作者：
Hiemer, Samantha E.;Szymaniak, Aleksander D.;Varelas, Xaralabos
背景：TGF 和 Hippo 通路在转移性乳腺癌中失调。结果：TGF 诱导的信号和核 TAZ/YAP 在转录水平上汇聚，控制对肿瘤发生重要的基因表达。结论：TAZ/YAP 是促进 TGF 诱导乳腺癌细胞致瘤表型所必需的。意义：我们的研究揭示了晚期乳腺癌中 TGF 通路与 TAZ/YAP 之间的新型串扰。不受控制的转化生长因子 (TGF) 信号传导可促进晚期乳腺癌的侵袭性转移特性。然而，人们对 TGF 介导的信号如何诱导致瘤事件知之甚少，特别是考虑到 TGF 在其他情况下具有明显的肿瘤抑制活性。在这里，我们证明转录调节因子 TAZ 和 YAP (TAZ/YAP) 作为 Hippo 通路的关键效应子，对于促进和维持乳腺癌细胞中 TGF 诱导的致瘤表型是必需的。 TAZ/YAP、TGF 激活的 SMAD2/3 和 TEAD 转录因子之间的相互作用揭示了这些因子在细胞核中的趋同作用。全基因组表达分析表明，TAZ/YAP、TEAD 和 TGF 诱导的信号协调特定的促肿瘤转录程序。重要的是，TAZ/YAP、TEAD 和 TGF 协同调节的基因（例如新靶点 NEGR1 和 UCA1）对于维持转移性乳腺癌细胞的致瘤活性是必需的。核 TAZ/YAP 还与 TGF 信号传导合作，促进非致瘤细胞的表型和转录变化，以克服 TGF 抑制效应。因此，我们的工作确定了乳腺癌细胞中核 TAZ/YAP 和 TGF 信号传导之间的串扰，揭示了对晚期疾病驱动机制的新见解。
Background: The TGF and Hippo pathways are dysregulated in metastatic breast cancers. Results: TGF-induced cues and nuclear TAZ/YAP converge at the transcriptional level to control gene expression important for tumorigenesis. Conclusion: TAZ/YAP are required to promote TGF-induced tumorigenic phenotypes in breast cancer cells. Significance: Our study reveals novel cross-talk between the TGF pathway and TAZ/YAP in late-stage breast cancers.Uncontrolled transforming growth factor- (TGF) signaling promotes aggressive metastatic properties in late-stage breast cancers. However, how TGF-mediated cues are directed to induce tumorigenic events is poorly understood, particularly given that TGF has clear tumor suppressing activity in other contexts. Here, we demonstrate that the transcriptional regulators TAZ and YAP (TAZ/YAP), key effectors of the Hippo pathway, are necessary to promote and maintain TGF-induced tumorigenic phenotypes in breast cancer cells. Interactions between TAZ/YAP, TGF-activated SMAD2/3, and TEAD transcription factors reveal convergent roles for these factors in the nucleus. Genome-wide expression analyses indicate that TAZ/YAP, TEADs, and TGF-induced signals coordinate a specific pro-tumorigenic transcriptional program. Importantly, genes cooperatively regulated by TAZ/YAP, TEAD, and TGF, such as the novel targets NEGR1 and UCA1, are necessary for maintaining tumorigenic activity in metastatic breast cancer cells. Nuclear TAZ/YAP also cooperate with TGF signaling to promote phenotypic and transcriptional changes in nontumorigenic cells to overcome TGF-repressive effects. Our work thus identifies cross-talk between nuclear TAZ/YAP and TGF signaling in breast cancer cells, revealing novel insight into late-stage disease-driving mechanisms.