VGLL4 targets a TCF4\u2013TEAD4 complex to coregulate Wnt and Hippo signalling in colorectal cancer

Shi Jiao,Lin Li,Chuanchuan Li,Qian Hao,Zhaocai Zhou,Haofei Miao,Lei Zhang

doi:10.1038/ncomms14058

Abstract

Concerted co-regulation of multiple signalling pathways is crucial for tissue homoeostasis and tumorigenesis. Here we report that VGLL4, a previously identified YAP antagonist, also functions as a regulator of Wnt/β-catenin signalling. The expression of VGLL4 is significantly downregulated in clinical colorectal carcinoma (CRC) specimens, positively associated with patient survival rate, and inversely correlated with the expression of Wnt target genes in CRCs. Knockdown of VGLL4 enhances proliferation and tumour formation of CRC cells. A designed peptide mimicking the function of VGLL4 effectively inhibits CRC progression in a de novo mouse model. Mechanistically, TEAD4 associates with TCF4 to form a complex and cobind target genes. VGLL4 targets this TEAD4–TCF4 complex to interfere the functional interplay between TEAD4 and TCF4, suppressing the transactivation of TCF4. Collectively, our study indicates that Wnt/β-catenin and Hippo-YAP signalling are directly linked at transcription factor-level, and VGLL4 can target a TEAD4–TCF4 complex to co-regulate both pathways.

Highlights

Concerted co-regulation of multiple signalling pathways is crucial for tissue homoeostasis and tumorigenesis
Instead of altering the subcellular localization of YAP and b-catenin, VGLL4 coregulates Wnt/b-catenin and Hippo-YAP signalling by targeting the functional interplay between TEAD4 and TCF4 that is essential for target gene transcription (Supplementary Figs 8 and 9)
We showed that VGLL4 negatively regulates Wnt/b-catenin signalling in a TEAD4-dependent manner

Summary

Introduction

Concerted co-regulation of multiple signalling pathways is crucial for tissue homoeostasis and tumorigenesis. Our study indicates that Wnt/b-catenin and Hippo-YAP signalling are directly linked at transcription factor-level, and VGLL4 can target a TEAD4–TCF4 complex to co-regulate both pathways. When the Wnt signalling is switched on, b-catenin translocates into the nucleus, where it interacts with the transcription factors TCF4/LEF1 to regulate the expression of the target genes. Piccolo and colleagues proposed that YAP/TAZ could be a constitutive component of the b-catenin destruction complex[26] They proposed that any retention of YAP/TAZ in the cytoplasm would promote destruction complex activity and inhibit Wnt/b-catenin signalling; in contrast, translocation of YAP/TAZ into the nucleus and away from the destruction complex would activate Wnt/b-catenin signalling. The potential cooperation between TCF4 and TEAD4, transcription factors of the Wnt/b-catenin and Hippo-YAP signalling pathways, remain poorly understood It is unclear whether other binding partners of TEAD4, such as VGLL proteins play a role in the co-regulation of Wnt/b-catenin and Hippo-YAP signalling. Based on a mechanistic dissection, we further developed a peptide that mimics VGLL4 function to treat gastric tumours

Methods

Results

Conclusion