Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis
Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis
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DOI：
10.1101/gad.173435.111
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发表时间：
2012-01-01
影响因子：
10.5
通讯作者：
Guan, Kun-Liang
中科院分区：
文献类型：
--
作者：
Zhao, Bin;Li, Li;Guan, Kun-Liang
细胞附着于细胞外基质（ECM）对细胞的极性、运动性和增殖等生理特性至关重要。在正常细胞中，失去对ECM的附着会引起一种特殊类型的细胞凋亡，称为细胞凋亡。癌细胞对anoikis的抵抗促进了它们在循环中的存活和向远处解剖部位的扩散，导致肿瘤转移。yes相关蛋白（YAP）转录辅激活因子是一种人类癌基因和器官大小的关键调节因子。Hippo肿瘤抑制通路磷酸化并抑制YAP。然而，人们对调节Hippo通路的信号知之甚少。在这里，我们报道通过细胞骨架重组，细胞脱离激活Hippo通路激酶Lats1/2，并导致YAP磷酸化和抑制。在未转化的细胞中，脱落诱导的YAP失活是anoikis所必需的，而在Hippo通路失调的癌细胞中，YAP和TAZ的敲低可以恢复anoikis。此外，我们提供的证据表明，Lats1/2表达水平在转移性前列腺癌中确实显著下调。我们的研究结果通过Hippo通路提供了细胞附着和anoikis之间的新联系，并在癌症治疗中具有重要意义。
Cell attachment to the extracellular matrix (ECM) is crucial to cell physiology such as polarity, motility, and proliferation. In normal cells, loss of attachment to the ECM induces a specific type of apoptosis, termed anoikis. Resistance to anoikis in cancer cells promotes their survival in circulation and dispersion to distant anatomic sites, leading to tumor metastasis. The Yes-associated protein (YAP) transcription coactivator is a human oncogene and a key regulator of organ size. The Hippo tumor suppressor pathway phosphorylates and inhibits YAP. However, little is known about the signals that regulate the Hippo pathway. Here we report that through cytoskeleton reorganization, cell detachment activates the Hippo pathway kinases Lats1/2 and leads to YAP phosphorylation and inhibition. The detachment-induced YAP inactivation is required for anoikis in non-transformed cells, whereas in cancer cells with deregulation of the Hippo pathway, knockdown of YAP and TAZ restores anoikis. Furthermore, we provided evidence that Lats1/2 expression level is indeed significantly down-regulated in metastatic prostate cancer. Our findings provide a novel connection between cell attachment and anoikis through the Hippo pathway and have important implications in cancer therapeutics.