Activation of the Hippo Pathway Is Required for Anoikis Free

Limitation of organ size by the Hippo tumor suppressor pathway maintains tissue homeostasis and prevents uncontrolled cell growth. The Hippo pathway kinases LATS1/2 phosphorylate the oncoprotein YAP, preventing its nuclear translocation and target gene activation. The upstream regulatory mechanisms of Hippo pathway kinase activation remain poorly understood, although previous reports have shown that high cell density and cell–cell contact promote Hippo pathway activation and subsequent YAP inhibition. Zhao and colleagues demonstrate that cell detachment also rapidly activates the Hippo pathway, leading to YAP phosphorylation and cytoplasmic sequestration that could be reversed with cell reattachment. Additionally, the use of cytoskeleton-disrupting agents revealed that loss of actin cytoskeleton integrity specifically promoted YAP phosphorylation and inhibition in a LATS1/2-dependent manner. In normal cells, cell detachment from the extracellular matrix induces a specific type of cell death called anoikis that is subverted in cancer cells to allow survival in the bloodstream during metastasis. The authors therefore hypothesized that YAP inhibition by LATS1/2 would activate anoikis in response to cell detachment. Indeed, ectopic expression of wild-type YAP or knockdown of LATS1/2 reduced anoikis in noncancerous mammary epithelial cells grown in suspension or ultra-low attachment by more than 50%, and ectopic expression of a nonphosphorylatable YAP mutant blocked anoikis completely. The authors provide additional evidence that decreased anoikis due to aberrations in the Hippo pathway promotes metastasis through their observation that LATS1/2 expression was significantly downregulated in metastatic prostate cancers compared with benign adjacent prostate tissue or localized primary prostate cancers. Collectively, these data suggest that targeted inhibition of YAP might be a useful approach for inducing anoikis and preventing metastasis in cancers with Hippo pathway abnormalities.

Zhao B, Li L, Wang L, Wang CY, Yu J, Guan KL. Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev 2012;26:54–68.

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