Selective Inhibition of STRN3-Containing PP2A Phosphatase Restores Hippo Tumor-Suppressor Activity in Gastric Cancer
- PMID: 32589942
- DOI: 10.1016/j.ccell.2020.05.019
Selective Inhibition of STRN3-Containing PP2A Phosphatase Restores Hippo Tumor-Suppressor Activity in Gastric Cancer
Abstract
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.
Keywords: Hippo-YAP signaling pathway; STRN3-derived Hippo-activating peptide (SHAP); gastric cancer; recover tumor-suppressor activity; therapeutic targeting of phosphatase.
Copyright © 2020 Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of Interests Z.Z., S.J., Y.T., G.F., W.W., and Y.Z. have filed a patent (CN111100189A) for the SHAP in China.
Comment in
-
Good Guy in Bad Company: How STRNs Convert PP2A into an Oncoprotein.Cancer Cell. 2020 Jul 13;38(1):20-22. doi: 10.1016/j.ccell.2020.06.011. Cancer Cell. 2020. PMID: 32663465
Similar articles
-
Reactivating Hippo by drug compounds to suppress gastric cancer and enhance chemotherapy sensitivity.J Biol Chem. 2024 Jun;300(6):107311. doi: 10.1016/j.jbc.2024.107311. Epub 2024 Apr 22. J Biol Chem. 2024. PMID: 38657866 Free PMC article.
-
Cryo-EM structure of the Hippo signaling integrator human STRIPAK.Nat Struct Mol Biol. 2021 Mar;28(3):290-299. doi: 10.1038/s41594-021-00564-y. Epub 2021 Feb 25. Nat Struct Mol Biol. 2021. PMID: 33633399 Free PMC article.
-
Good Guy in Bad Company: How STRNs Convert PP2A into an Oncoprotein.Cancer Cell. 2020 Jul 13;38(1):20-22. doi: 10.1016/j.ccell.2020.06.011. Cancer Cell. 2020. PMID: 32663465
-
Okadaic Acid: a tool to study the hippo pathway.Mar Drugs. 2013 Mar 14;11(3):896-902. doi: 10.3390/md11030896. Mar Drugs. 2013. PMID: 23493077 Free PMC article. Review.
-
The Hippo pathway as a drug target in gastric cancer.Cancer Lett. 2018 Apr 28;420:14-25. doi: 10.1016/j.canlet.2018.01.062. Epub 2018 Jan 31. Cancer Lett. 2018. PMID: 29408652 Review.
Cited by
-
Interaction of the Hippo Pathway and Phosphatases in Tumorigenesis.Cancers (Basel). 2020 Aug 27;12(9):2438. doi: 10.3390/cancers12092438. Cancers (Basel). 2020. PMID: 32867200 Free PMC article. Review.
-
Hippo pathway dysregulation in gastric cancer: from Helicobacter pylori infection to tumor promotion and progression.Cell Death Dis. 2023 Jan 12;14(1):21. doi: 10.1038/s41419-023-05568-8. Cell Death Dis. 2023. PMID: 36635265 Free PMC article. Review.
-
SHOX2 promotes prostate cancer proliferation and metastasis through disruption of the Hippo-YAP pathway.iScience. 2023 Aug 11;26(9):107617. doi: 10.1016/j.isci.2023.107617. eCollection 2023 Sep 15. iScience. 2023. PMID: 37664594 Free PMC article.
-
LncRNA KTN1-AS1 facilitates esophageal squamous cell carcinoma progression via miR-885-5p/STRN3 axis.Genes Genomics. 2024 Feb;46(2):241-252. doi: 10.1007/s13258-023-01451-0. Epub 2023 Sep 25. Genes Genomics. 2024. PMID: 37747640
-
Inhibitors Targeting YAP in Gastric Cancer: Current Status and Future Perspectives.Drug Des Devel Ther. 2021 Jun 9;15:2445-2456. doi: 10.2147/DDDT.S308377. eCollection 2021. Drug Des Devel Ther. 2021. PMID: 34140763 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical
Molecular Biology Databases
Research Materials
Miscellaneous