A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer

Shi Jiao; Huizhen Wang; Zhubing Shi; Aimei Dong; Wenjing Zhang; Xiaomin Song; Feng He; Yicui Wang; Zhenzhen Zhang; Wenjia Wang; Xin Wang; Tong Guo; Peixue Li; Yun Zhao; Hongbin Ji; Lei Zhang; Zhaocai Zhou

doi:10.1016/j.ccr.2014.01.010

A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer

Cancer Cell. 2014 Feb 10;25(2):166-80. doi: 10.1016/j.ccr.2014.01.010.

Authors

Shi Jiao¹, Huizhen Wang¹, Zhubing Shi¹, Aimei Dong², Wenjing Zhang¹, Xiaomin Song¹, Feng He¹, Yicui Wang¹, Zhenzhen Zhang¹, Wenjia Wang¹, Xin Wang¹, Tong Guo¹, Peixue Li¹, Yun Zhao¹, Hongbin Ji³, Lei Zhang⁴, Zhaocai Zhou⁵

Affiliations

¹ National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
² Department of Gastroenterology and Internal Medicine, Nanjing Xiaguan Hospital, Nanjing, Jiangsu 210085, China.
³ National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China. Electronic address: hbji@sibcb.ac.cn.
⁴ National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China. Electronic address: rayzhang@sibcb.ac.cn.
⁵ National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China. Electronic address: zczhou@sibcb.ac.cn.

PMID: 24525233
DOI: 10.1016/j.ccr.2014.01.010

Abstract

The Hippo pathway has been implicated in suppressing tissue overgrowth and tumor formation by restricting the oncogenic activity of YAP. However, transcriptional regulators that inhibit YAP activity have not been well studied. Here, we uncover clinical importance for VGLL4 in gastric cancer suppression and find that VGLL4 directly competes with YAP for binding TEADs. Importantly, VGLL4's tandem Tondu domains are not only essential but also sufficient for its inhibitory activity toward YAP. A peptide mimicking this function of VGLL4 potently suppressed tumor growth in vitro and in vivo. These findings suggest that disruption of YAP-TEADs interaction by a VGLL4-mimicking peptide may be a promising therapeutic strategy against YAP-driven human cancers.

Publication types

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

MeSH terms

Animals
Antimetabolites, Antineoplastic / pharmacology
Case-Control Studies
Cell Cycle Proteins
Cell Survival
DNA-Binding Proteins / metabolism*
Female
Fluorouracil / pharmacology
Gastric Mucosa / metabolism
Humans
Immunoenzyme Techniques
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred ICR
Middle Aged
Molecular Mimicry*
Muscle Proteins / metabolism*
Neoplasm Invasiveness
Neoplasm Staging
Nuclear Proteins / antagonists & inhibitors*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Peptide Fragments / pharmacology*
Protein Conformation
Stomach / pathology
Stomach Neoplasms / genetics
Stomach Neoplasms / metabolism
Stomach Neoplasms / prevention & control*
TEA Domain Transcription Factors
Tissue Array Analysis
Transcription Factors / antagonists & inhibitors*
Transcription Factors / chemistry
Transcription Factors / genetics
Transcription Factors / metabolism*

Substances

Antimetabolites, Antineoplastic
Cell Cycle Proteins
DNA-Binding Proteins
Muscle Proteins
Nuclear Proteins
Peptide Fragments
TEA Domain Transcription Factors
TEAD4 protein, human
Transcription Factors
VGLL4 protein, human
YY1AP1 protein, human
Fluorouracil