Hippo kinases regulate cell junctions to inhibit tumor metastasis in response to oxidative stress

Reactive oxygen species (ROS) are key regulators in cell proliferation, survival, tumor initiation and development. However, the role of ROS in tumor metastasis is less clear. Here, we show that oxidative stress inhibited tumor metastasis via activation of Hippo kinase MST1/2, which led to the phosphorylation and nuclear accumulation of FoxO3a, resulting in upregulation of ΔNp63α expression and suppression of cell migration independent of YAP. Strikingly, while loss of MST1 led to and disruption of cell-cell junction exemplified by reduced E-cadherin expression, resulting in scattered cell growth, loss of MST2 led to disruption of cell-matrix adhesion as evidenced by reduced integrin β4, resulting in increased cell migration and tumor metastasis. Furthermore, expression of MST1 and MST2 was down-regulated in human breast carcinoma. Furthermore, oxidative stress inhibited HER2-or PI3K-mediated tumor metastasis via the MST2-FoxO3a-ΔNp63α pathway. Together, these results that this noncanonical Hippo MST2-FoxO3a-ΔNp63α pathway may play a critical role in ROS-mediated regulation of cell migration and tumor metastasis.