Selective Inhibition of STRN3-Containing PP2A Phosphatase Restores Hippo Tumor-Suppressor Activity in Gastric Cancer
Selective Inhibition of STRN3-Containing PP2A Phosphatase Restores Hippo Tumor-Suppressor Activity in Gastric Cancer
复制标题
选择性抑制含有 STRN3 的 PP2A 磷酸酶可恢复 Hippo 胃癌的肿瘤抑制活性
DOI：
10.1016/j.ccell.2020.05.019
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发表时间：
2020-07-13
期刊：
影响因子：
50.3
通讯作者：
Zhou, Zhaocai
中科院分区：
文献类型：
--
作者：
Tang, Yang;Fang, Gemin;Zhou, Zhaocai
Hippo肿瘤抑制活性的丧失和雅普过度激活在癌症中常见。Hippo激酶MST 1/2的失活突变并不常见，目前仍不清楚它们的活性在肿瘤发生过程中是如何被关闭的。我们鉴定了STRN 3作为蛋白磷酸酶2A（PP 2A）的必需调节亚基，其募集MST 1/2并促进其去磷酸化，这导致雅普活化。我们还确定了胃癌中STRN 3的上调与雅普激活和不良预后相关。基于这种机制的理解和结构指导的药物化学的帮助下，我们开发了一种高度选择性的肽抑制剂，STRN 3衍生的Hippo激活肽，或SHAP，其破坏STRN 3-PP 2Aa相互作用并重新激活Hippo肿瘤抑制因子，抑制雅普激活，并在体内具有抗肿瘤作用。
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.