VGLL4 targets a TCF4–TEAD4 complex to coregulate Wnt and Hippo signalling in colorectal cancer

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.

Wnt target genes and where to find them

“…Consistent with this, genome-wide surveys of TCF or β-cat binding in vertebrates reveal the presence of several TF binding site motifs besides the TCF site consensus 1, 30, 39, 77, 78 . Other TFs have been reported to co-localize with TCFs 36, 38, 39, 79, 80 , and in the cases of Cdx2 79 , Sp5/8 81 , and TEAD TFs 82 , a co-dependency with TCFs or β-cat for chromatin association has been reported. In addition, TCF binding to chromatin is highly cell type specific 36 and is dynamic over time in the same cell type 38, 39 .…”

Regulation of the Hippo Pathway Transcription Factor TEAD

“…VGLL4 binding to TEAD4 inhibits TEAD4-TCF4 driven target gene expression as it does for TEAD-YAP/TAZ target gene expression, but does not compete with TCF4 for TEAD binding. Instead, VGLL4 inhibition of TEAD4-TCF4 transcriptional activity is due to formation of a TEAD4/TCF4/VGLL4 ternary complex [41]. The p160 family of steroid receptor coactivators was also identified to interact with TEAD.…”

Reaping Wnt after calming Hippo: Wnt and Hippo signaling cross paths in lung cancer

“…Complexes of YAP1/TEAD and betacatenin/TCF have been detected and a subset of Wnt/ beta-catenin target genes may rely on nuclear YAP1/ TEAD complexes for full induction in response to Wnt ligands (18). These data suggest that in addition to the complex interactions between Wnt and Hippo signaling components in the cytoplasm, both pathways can cooperate in the nucleus to execute gene expression programs that affect proliferation, organ size, tissue repair, and tumor growth.…”

“…These data highlight how interactions between pathways can result in, at first glance, paradoxical findings: e.g., the signaling of pro-tumorigenic pathways Wnt and YAP1 can have opposing effects on tumor growth (18). Furthermore, in some experimental systems a majority of beta-catenin regulated genes are dependent on WWTR1 (TAZ) (20).…”

“…Furthermore, in some experimental systems a majority of beta-catenin regulated genes are dependent on WWTR1 (TAZ) (20). Although this reliance on Wnt target genes appears to be dependent on cytoplasmic interactions between betacatenin and WWTR1 (TAZ), co-regulation of a subset of Wnt target genes can also be achieved by the cooperation of beta-catenin/TCF and YAP1/WWTR1/TEAD transcriptional complexes (18). On the other hand, Park et al observed in their experiments that activation of noncanonical Wnt signaling-i.e., Wnt signaling independent of beta-catenin-resulted in increased levels of WWTR1 and YAP1, increased expression of YAP1 target genes, increased TEAD-dependent migration and differentiation, and expression of Wnt signaling inhibitors, all of which leads to reduced canonical Wnt signaling (21).…”