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

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

doi:10.1016/j.ccell.2020.05.019

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

Cancer Cell. 2020 Jul 13;38(1):115-128.e9. doi: 10.1016/j.ccell.2020.05.019. Epub 2020 Jun 25.

Authors

Yang Tang¹, Gemin Fang², Fenghua Guo³, Hui Zhang⁴, Xiaoxu Chen², Liwei An⁵, Min Chen⁵, Li Zhou⁶, Wenjia Wang⁴, Tiantian Ye⁴, Lei Zhou⁷, Pingping Nie⁴, Haijun Yu⁷, Moubin Lin⁸, Yun Zhao⁴, Xinhua Lin⁹, Zengqiang Yuan¹⁰, Shi Jiao¹¹, Zhaocai Zhou¹²

Affiliations

¹ 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.
² Institutes of Physical Science and Information Technology, Anhui University, Hefei 230601, China.
³ Department of General Surgery, Hua'shan Hospital, Fudan University Shanghai Medical College, Shanghai 200040, China.
⁴ 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.
⁵ 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.
⁶ 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; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
⁷ State Key Laboratory of Drug Research and Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201203, China.
⁸ Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China.
⁹ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200438, China.
¹⁰ Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
¹¹ 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. Electronic address: jiaoshi@sibcb.ac.cn.
¹² State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200438, China. Electronic address: zczhou@sibcb.ac.cn.

PMID: 32589942
DOI: 10.1016/j.ccell.2020.05.019

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Autoantigens / genetics
Autoantigens / metabolism*
Calmodulin-Binding Proteins / genetics
Calmodulin-Binding Proteins / 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
Protein Phosphatase 2 / genetics
Protein Phosphatase 2 / metabolism*
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Signal Transduction / drug effects
Signal Transduction / genetics
Stomach Neoplasms / genetics
Stomach Neoplasms / metabolism*
Stomach Neoplasms / prevention & control
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*
Xenograft Model Antitumor Assays / methods

Substances

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