选择性抑制包含 STRN3 的 PP2A 磷酸酶可恢复胃癌中的 Hippo 肿瘤抑制活性。
Selective Inhibition of STRN3-Containing PP2A Phosphatase Restores Hippo Tumor-Suppressor Activity in Gastric Cancer.
机构信息
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Tongji University Cancer Center, Postdoctoral Station of Clinical Medicine, Department of Medical Ultrasound, Ultrasound Research and Education Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Institutes of Physical Science and Information Technology, Anhui University, Hefei 230601, China.
出版信息
Cancer Cell. 2020 Jul 13;38(1):115-128.e9. doi: 10.1016/j.ccell.2020.05.019. Epub 2020 Jun 25.
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.
Hippo 肿瘤抑制因子活性丧失和 YAP 的过度激活在癌症中普遍存在。Hippo 激酶 MST1/2 的失活突变并不常见，其活性在肿瘤发生过程中如何失活仍不清楚。我们鉴定出 STRN3 是蛋白磷酸酶 2A（PP2A）的一个必需调节亚基，它可以募集 MST1/2 并促进其去磷酸化，从而激活 YAP。我们还发现胃癌中 STRN3 的上调与 YAP 的激活和预后不良相关。基于这一机制理解，并借助结构导向的药物化学，我们开发了一种高度选择性的肽抑制剂，即 STRN3 衍生的 Hippo 激活肽（SHAP），它可以破坏 STRN3-PP2Aα 的相互作用，重新激活 Hippo 肿瘤抑制因子，抑制 YAP 的激活，并在体内具有抗肿瘤作用。
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