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Vestigial-like family member 3 (VGLL3), a cofactor for TEAD transcription factors, promotes cancer cell proliferation by activating the Hippo pathway.

ABSTRACT: Vestigial-like 3 (VGLL3) is a member of the VGLL family, whose members serve as cofactors for TEA domain-containing transcription factors (TEADs). TEADs promote tissue and tumor development together with the cofactors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Although VGLL3 is involved in tumor cell proliferation, its relationship with TEADs and YAP/TAZ remains largely unknown. To close this research gap, here we established tumor cells stably expressing VGLL3 and found that they exhibit enhanced proliferation. Notably, YAP and TAZ were inactivated in the VGLL3-expressing cells, coinciding with activation of the Hippo pathway, which suppresses YAP/TAZ activities. VGLL3 in combination with TEADs promoted expression of the Hippo pathway components large tumor suppressor kinase (LATS2) and angiomotin-like 2 (AMOTL2). VGLL3 was highly expressed in malignant breast tumor cells and osteosarcoma cells, and VGLL3 knockdown increased nuclear localization of YAP and TAZ. Knockdown of LATS2 or AMOTL2, as well as VGLL3 knockdown, repressed proliferation of breast tumor cells. Together, these results suggest that VGLL3 together with TEADs promotes cell proliferation by activating the Hippo pathway through LATS2 and AMOTL2, leading to YAP/TAZ inactivation.

SUBMITTER: Hori N

PROVIDER: S-EPMC7324512 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors.

Project description:The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signaling pathway. Transcriptional activation of these proteins occurs upon binding to the co-activator YAP/TAZ whose entry into the nucleus is regulated by Lats1/2 kinase. In recent years, it has become apparent that the dysregulation and/or overexpression of Hippo pathway effectors is implicated in a wide range of cancers, including prostate, gastric and liver cancer. A large body of work has been dedicated to understanding the therapeutic potential of modulating the phosphorylation and localization of YAP/TAZ. However, YAP/TAZ are considered to be natively unfolded and may be intractable as drug targets. Therefore, TEAD proteins present themselves as an excellent therapeutic target for intervention of the Hippo pathway. This review summarizes the functional role of TEAD proteins in cancer and assesses the therapeutic potential of antagonizing TEAD function in vivo.

| S-EPMC5876656 | biostudies-literature

The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control.

Project description:The Hippo (Hpo) signaling pathway governs cell growth, proliferation, and apoptosis by controlling key regulatory genes that execute these processes; however, the transcription factor of the pathway has remained elusive. Here we provide evidence that the TEAD/TEF family transcription factor Scalloped (Sd) acts together with the coactivator Yorkie (Yki) to regulate Hpo pathway-responsive genes. Sd and Yki form a transcriptional complex whose activity is inhibited by Hpo signaling. Sd overexpression enhances, whereas its inactivation suppresses, tissue overgrowth caused by Yki overexpression or tumor suppressor mutations in the Hpo pathway. Inactivation of Sd diminishes Hpo target gene expression and reduces organ size, whereas a constitutively active Sd promotes tissue overgrowth. Sd promotes Yki nuclear localization, whereas Hpo signaling retains Yki in the cytoplasm by phosphorylating Yki at S168. Finally, Sd recruits Yki to the enhancer of the pathway-responsive gene diap1, suggesting that diap1 is a direct transcriptional target of the Hpo pathway.

| S-EPMC2292673 | biostudies-literature

IFN-?-response mediator GBP-1 represses human cell proliferation by inhibiting the Hippo signaling transcription factor TEAD.

Project description:Interferon-gamma (IFN-?) is a pleiotropic cytokine that exerts important functions in inflammation, infectious diseases, and cancer. The large GTPase human guanylate-binding protein 1 (GBP-1) is among the most strongly IFN-?-induced cellular proteins. Previously, it has been shown that GBP-1 mediates manifold cellular responses to IFN-? including the inhibition of proliferation, spreading, migration, and invasion and through this exerts anti-tumorigenic activity. However, the mechanisms of GBP-1 anti-tumorigenic activities remain poorly understood. Here, we elucidated the molecular mechanism of the human GBP-1-mediated suppression of proliferation by demonstrating for the first time a cross-talk between the anti-tumorigenic IFN-? and Hippo pathways. The ?9-helix of GBP-1 was found to be sufficient to inhibit proliferation. Protein-binding and molecular modeling studies revealed that the ?9-helix binds to the DNA-binding domain of the Hippo signaling transcription factor TEA domain protein (TEAD) mediated by the 376VDHLFQK382 sequence at the N-terminus of the GBP-1-?9-helix. Mutation of this sequence resulted in abrogation of both TEAD interaction and suppression of proliferation. Further on, the interaction caused inhibition of TEAD transcriptional activity associated with the down-regulation of TEAD-target genes. In agreement with these results, IFN-? treatment of the cells also impaired TEAD activity, and this effect was abrogated by siRNA-mediated inhibition of GBP-1 expression. Altogether, this demonstrated that the ?9-helix is the proliferation inhibitory domain of GBP-1, which acts independent of the GTPase activity through the inhibition of the Hippo transcription factor TEAD in mediating the anti-proliferative cell response to IFN-?.

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Zebrafish Vestigial Like Family Member 4b Is Required for Valvulogenesis Through Sequestration of Transcription Factor Myocyte Enhancer Factor 2c.

Project description:A variety of cardiac transcription factors/cofactors, signaling pathways, and downstream structural genes integrate to form the regulatory hierarchies to ensure proper cardiogenesis in vertebrate. Major interaction proteins of the transcription cofactor vestigial like family member 4 (VGLL4) include myocyte enhancer factor 2 (MEF2) and TEA domain transcription factors (TEAD), both of which play important roles in embryonic cardiac development and in adulthood. In this study, we identified that the deficiency of zebrafish vgll4b paralog, a unique family member expressed in developing heart, led to an impaired valve development. Mechanistically, in vgll4b mutant embryos the disruption of Vgll4b-Mef2c complex, rather than that of Vgll4b-Tead complex, resulted in an aberrant expression of krüppel-like factor 2a (klf2a) in endocardium. Such misexpression of klf2a eventually evoked the valvulogenesis defects. Our findings suggest that zebrafish Vgll4b plays an important role in modulating the transcription activity of Mef2c on klf2a during valve development in a blood-flow-independent manner.

| S-EPMC6874126 | biostudies-literature

Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation.

Project description:The Hippo pathway controls organ size and tissue homeostasis, with deregulation leading to cancer. The core Hippo components in mammals are composed of the upstream serine/threonine kinases Mst1/2, MAPK4Ks and Lats1/2. Inactivation of these upstream kinases leads to dephosphorylation, stabilization, nuclear translocation and thus activation of the major functional transducers of the Hippo pathway, YAP and its paralogue TAZ. YAP/TAZ are transcription co-activators that regulate gene expression primarily through interaction with the TEA domain DNA-binding family of transcription factors (TEAD). The current paradigm for regulation of this pathway centres on phosphorylation-dependent nucleocytoplasmic shuttling of YAP/TAZ through a complex network of upstream components. However, unlike other transcription factors, such as SMAD, NF-κB, NFAT and STAT, the regulation of TEAD nucleocytoplasmic shuttling has been largely overlooked. In the present study, we show that environmental stress promotes TEAD cytoplasmic translocation via p38 MAPK in a Hippo-independent manner. Importantly, stress-induced TEAD inhibition predominates YAP-activating signals and selectively suppresses YAP-driven cancer cell growth. Our data reveal a mechanism governing TEAD nucleocytoplasmic shuttling and show that TEAD localization is a critical determinant of Hippo signalling output.

| S-EPMC5541894 | biostudies-literature

Immunometabolic function of the transcription cofactor VGLL3 provides an evolutionary rationale for sexual dimorphism in autoimmunity.

Project description:Sexual dimorphism is exhibited remarkably in the female predominance of autoimmune diseases (e.g. systemic lupus erythematosus, female-to-male ratio 9 : 1). To understand the female bias in autoimmunity, we focused on vestigial-like family member 3 (VGLL3), a molecule with increased expression in females and known to promote autoimmunity. We report that VGLL3 mediates the cellular stress response by upregulating p53 and IL-17C. Energy stress allows VGLL3 to be induced by IFNα, which ultimately leads to p53-dependent, lupus-associated, inflammatory cell death. Our results suggest that female-biased expression of VGLL3 helps cells adapt to metabolic stress, which, intriguingly, is known as a significant challenge during the evolution of placental mammals due to the need to feed a developing embryo. The findings also uncover the importance of maintaining metabolic homeostasis in the prevention of autoimmunity.

| S-EPMC7722229 | biostudies-literature

Angiomotin stabilization by tankyrase inhibitors antagonizes constitutive TEAD-dependent transcription and proliferation of human tumor cells with Hippo pathway core component mutations.

Project description:The evolutionarily conserved Hippo inhibitory pathway plays critical roles in tissue homeostasis and organ size control, while mutations affecting certain core components contribute to tumorigenesis. Here we demonstrate that proliferation of Hippo pathway mutant human tumor cells exhibiting high constitutive TEAD transcriptional activity was markedly inhibited by dominant negative TEAD4, which did not inhibit the growth of Hippo wild-type cells with low levels of regulatable TEAD-mediated transcription. The tankyrase inhibitor, XAV939, identified in a screen for inhibitors of TEAD transcriptional activity, phenocopied these effects independently of its other known functions by stabilizing angiomotin and sequestering YAP in the cytosol. We also identified one intrinsically XAV939 resistant Hippo mutant tumor line exhibiting lower and less durable angiomotin stabilization. Thus, angiomotin stabilization provides a new mechanism for targeting tumors with mutations in Hippo pathway core components as well as a biomarker for sensitivity to such therapy.

| S-EPMC5045355 | biostudies-literature

Vestigial like family protein

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-05-22 | GSE260784 | GEO

Hippo Component TAZ Functions as a Co-repressor and Negatively Regulates ?Np63 Transcription through TEA Domain (TEAD) Transcription Factor.

Project description:Transcriptional co-activator with a PDZ binding domain (TAZ) is a WW domain-containing transcriptional co-activator and a core component of an emerging Hippo signaling pathway that regulates organ size, tumorigenesis, metastasis, and drug resistance. TAZ regulates these biological functions by up-regulating downstream cellular genes through transactivation of transcription factors such as TEAD and TTF1. To understand the molecular mechanisms underlying TAZ-induced tumorigenesis, we have recently performed a gene expression profile analysis by overexpressing TAZ in mammary cells. In addition to the TAZ-up-regulated genes that were confirmed in our previous studies, we identified a large number of cellular genes that were down-regulated by TAZ. In this study, we have confirmed these down-regulated genes (including cytokines, chemokines, and p53 gene family members) as bona fide downstream transcriptional targets of TAZ. By using human breast and lung epithelial cells, we have further characterized ?Np63, a p53 gene family member, and shown that TAZ suppresses ?Np63 mRNA, protein expression, and promoter activity through interaction with the transcription factor TEAD. We also show that TEAD can inhibit ?Np63 promoter activity and that TAZ can directly interact with ?Np63 promoter-containing TEAD binding sites. Finally, we provide functional evidence that down-regulation of ?Np63 by TAZ may play a role in regulating cell migration. Altogether, this study provides novel evidence that the Hippo component TAZ can function as a co-repressor and regulate biological functions by negatively regulating downstream cellular genes.

| S-EPMC4505436 | biostudies-literature

MicroRNA-301b-3p contributes to tumour growth of human hepatocellular carcinoma by repressing vestigial like family member 4.

Project description:MicroRNAs (miRNAs) are key regulators in the tumour growth and metastasis of human hepatocellular carcinoma (HCC). Increasing evidence suggests that miR-301b-3p functions as a driver in various types of human cancer. However, the expression pattern of miR-301b-3p and its functional role as well as underlying molecular mechanism in HCC remain poorly known. Our study found that miR-301b-3p expression was significantly up-regulated in HCC tissues compared to adjacent non-tumour tissues. Clinical association analysis revealed that the high level of miR-301b-3p closely correlated with large tumour size and advanced tumour-node-metastasis stages. Importantly, the high miR-301b-3p level predicted a prominent poorer overall survival of HCC patients. Knockdown of miR-301b-3p suppressed cell proliferation, led to cell cycle arrest at G2/M phase and induced apoptosis of Huh7 and Hep3B cells. Furthermore, miR-301b-3p knockdown suppressed tumour growth of HCC in mice. Mechanistically, miR-301b-3p directly bond to 3'UTR of vestigial like family member 4 (VGLL4) and negatively regulated its expression. The expression of VGLL4 mRNA was down-regulated and inversely correlated with miR-301b-3p level in HCC tissues. Notably, VGLL4 knockdown markedly repressed cell proliferation, resulted in G2/M phase arrest and promoted apoptosis of HCC cells. Accordingly, VGLL4 silencing rescued miR-301b-3p knockdown attenuated HCC cell proliferation, cell cycle progression and apoptosis resistance. Collectively, our results suggest that miR-301b-3p is highly expressed in HCC. miR-301b-3p facilitates cell proliferation, promotes cell cycle progression and inhibits apoptosis of HCC cells by repressing VGLL4.

| S-EPMC6653225 | biostudies-literature

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