Selective Inhibition of STRN3-Containing PP2A Phosphatase Restores Hippo Tumor-Suppressor Activity in Gastric Cancer

Loss of Hippo tumor-suppressor activity and hyperactivation of YAP are commonly observed in cancers. Inactivating mutations of Hippo kinases MST1/2 are uncommon, and it remains unclear how their activity is turned off during tumorigenesis. We identified STRN3 as an essential regulatory subunit of protein phosphatase 2A (PP2A) that recruits MST1/2 and promotes its dephosphorylation, which results in YAP activation. We also identified STRN3 upregulation in gastric cancer correlated with YAP activation and poor prognosis. Based on this mechanistic understanding and aided by structure-guided medicinal chemistry, we developed a highly selective peptide inhibitor, STRN3-derived Hippo-activating peptide, or SHAP, which disrupts the STRN3-PP2Aa interaction and reactivates the Hippo tumor suppressor, inhibits YAP activation, and has antitumor effects in vivo. [Display omitted] •The STRN3-containing PP2A phosphatase turns off Hippo tumor-suppressor activity•Upregulated STRN3 correlates with hyperactivation of YAP and poor prognosis of GC•STRN3 binds PP2Aa on a site different from that of other regulatory subunits•A rationally designed selective PP2A inhibitor SHAP reactivates MST1/2 to treat GC Tang et al. show that MST1/2 kinases are dephosphorylated by a STRN3-containing PP2A complex, thus inhibiting the Hippo pathway and activating YAP. They develop a therapeutic peptide that obstructs the STRN3-PP2A interaction, inhibits YAP activation, and shows efficacy in gastric cancer models.