Multiple Roles of Vestigial-Like Family Members in Tumor Development

Abstract

Vestigial-like family (VGLL) members are mammalian orthologs of vestigial gene in Drosophila, and they consist of four homologs (VGLL1-4). VGLL members have TDU motifs that are binding regions to TEA/ATSS-DNA-binding domain transcription factor (TEAD). Through TDU motifs, VGLL members act as transcriptional cofactors for TEAD. VGLL1-3 have single TDU motif, whereas VGLL4 has two tandem TDU motifs, suggesting that VGLL4 has distinct molecular functions among this family. Although molecular and physiological functions of VGLL members are still obscure, emerging evidence has shown that these members are involved in tumor development. Gene alterations and elevated expression of VGLL1-3 were observed in various types of tumors, and VGLL1-3 have been shown to possess tumorigenic functions. In contrast, down-regulation of VGLL4 was detected in various tumors, and the tumor-suppressing role of VGLL4 has been demonstrated. In this review, we summarize the recently identified multiple roles of VGLL members in tumor development and provide important and novel insights regarding tumorigenesis.

Keywords: Hippo; TAZ; TEAD; VGLL; YAP; vestigial.

Figure 1

Multiple roles of VGLL members in tumor development. (A) Schematic representations of VGLL family proteins. Domain architecture is based on (7). CDK1-mediated phosphorylation sites (8) and a p300-mediated acetylation site (9) are shown on the VGLL4 structure. TDU, Tondu motif. (B) Overexpression of VGLL1 promotes anchorage-independent growth of prostate tumor cell lines through the induction of IGFBP5. VGLL1 expression was increased by the PI3K-AKT-β-catenin pathway and induced metastasis via MMP9 expression in gastric tumor. VGLL1 was induced by HPV infection, and VGLL1 contributed to HPV early gene expression. Estrogen receptor (ER) repressed VGLL1 expression in breast tumor. (C) VGLL2 fusion genes (VGLL2-CITED2 and VGLL2-NCOA2) were identified in pediatric spindle and sclerosing rhabdomyosarcoma. Although the tumorigenicity of these genes is obscure, it has been suggested that these genes affect gene expression signatures in tumor. (D) VGLL3 gene amplification was detected in myxoinflammatory fibroblastic sarcoma and soft tissue sarcoma, and VGLL3 was involved in the proliferation of sarcoma cells. VGLL3 expression showed positive correlation with poor prognosis in gastric tumor patients, and the activation of MAPK, JAK-STAT, WNT pathways as well as enhanced immune infiltrates were observed in VGLL3-high tumor. VGLL3 expression was induced by TGF-β-stimulation in a histone-modification dependent manner. (E) VGLL4 as a tumor suppressor through competition with YAP/TAZ for TEAD-binding in various tumors. Inactivation of VGLL4 was caused by microRNA-mediated gene silencing or CDK1-mediated phosphorylation. USP11 stabilized VGLL4 and enhanced its tumor-suppressing role. IRF2BP2 had both positive and negative effects on VGLL4. TCF4, STAT3, β-catenin, and cIAPs are also targets of VGLL4-mediated suppression.