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.

• Authors: Yang Tang, Gemin Fang, Fenghua Guo, Hui Zhang, Xiaoxu Chen, Liwei An, Min Chen, Li Zhou, Wenjia Wang, Tiantian Ye, Lei Zhou, Pingping Nie, Haijun Yu, Moubin Lin, Yun Zhao, Xinhua Lin, Zengqiang Yuan, Shi Jiao, Zhaocai Zhou
• Journal: Cancer cell (Cancer Cell) Vol. 38 Issue 1 Pg. 115-128.e9 (07 13 2020) ISSN: 1878-3686 [Electronic] United States
• PMID: 32589942 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Autoantigens
• Calmodulin-Binding Proteins
• Peptides
• STRN3 protein, human
• Tumor Suppressor Proteins
• Protein Serine-Threonine Kinases
• Protein Phosphatase 2

Topics

• Amino Acid Sequence
• Animals
• Autoantigens (genetics, metabolism)
• Calmodulin-Binding Proteins (genetics, metabolism)
• Cell Line, Tumor
• Female
• Hippo Signaling Pathway
• Humans
• Kaplan-Meier Estimate
• Male
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Peptides (pharmacology)
• Protein Phosphatase 2 (antagonists & inhibitors, genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Signal Transduction (drug effects, genetics)
• Stomach Neoplasms (genetics, metabolism, prevention & control)
• Tumor Suppressor Proteins (genetics, metabolism)
• Xenograft Model Antitumor Assays (methods)