Vestigial‐like family member 3 stimulates cell motility by inducing high‐mobility group AT‐hook 2 expression in cancer cells

Abstract

Vestigial‐like family member 3 (VGLL3) is a cofactor for TEA domain transcription factors (TEADs). Although VGLL3 is known to be highly expressed and stimulate cell proliferation in mesenchymal cancer cells, its involvement in mesenchymal phenotypes is largely unknown. In this study, we found that VGLL3 promotes epithelial‐to‐mesenchymal transition (EMT)‐like phenotypic changes. We found that A549 human lung cancer cells stably expressing VGLL3 exhibit spindle‐like morphological changes, reduction in the epithelial marker E‐cadherin and induction of the mesenchymal marker Snail. Notably, VGLL3‐expressing cells exhibited enhanced motility. The DNA‐binding protein high‐mobility group AT‐hook 2 (HMGA2) was found to be a target of the VGLL3‐TEAD4 complex, and HMGA2 knockdown repressed EMT‐like phenotypic changes in VGLL3‐expressing cells. VGLL3‐dependent phenotypic changes are involved in transforming growth factor‐β (TGF‐β)‐induced EMT progression. VGLL3 or HMGA2 knockdown repressed the motility of the mesenchymal breast cancer MDA‐MB‐231 cells. Importantly, high levels of VGLL3 expression were shown to have a positive correlation with poor prognosis in various human cancers, such as breast, colon, ovarian, head and neck, pancreatic, renal, gastric and cervical cancers. These results suggest that VGLL3 promotes EMT‐like cell motility by inducing HMGA2 expression and accelerates cancer progression.

A complex mechanism translating variation of a simple genetic architecture into alternative life-histories

“…Blue included vgll3 , vgll4 , tead1b , tead2 , nr5a1 , cyp17a1 , me3 , sema3d , Wnt4 , among other genes (Table S3). Blue module expression pattern was consistent with a decreasing expression of genes inhibiting epithelial-to-mesenchymal transition (EMT, e.g., cadherin , protocadherin , and Wnt4 ) towards the breeding season, consistent with a role of vgll3 in the regulation of EMT 40 . Vgll3 was among the most connected genes within blue with 1490 neighbors of the 3563 genes in blue in total (75 th quantile, Fig 2D).…”

Gene Regulatory Network Characterization of Gastric Cancer’s Histological Subtypes: Distinctive Biological and Clinically Relevant Master Regulators

“…Indeed, we speculated that the negative impact of VGLL3 activity on a patient's prognosis could be related to its role in modulating EMT, collagen synthesis and extracellular matrix organization as highlighted by the intersection of the gene network and several gene sets. Its biological activity has also been demonstrated in vitro by Hori N et al, who described the promotion of an EMT-like phenotype and an increased motility in VGLL3-expressing lung cancer cells [46]. SNAI2 is another enriched MR.…”

Successful placentation in human pregnancy is regulated by reciprocal interactions between maternal uterine NK cells and fetal placental trophoblast

“…Genes upregulated in EVT after exposure to uNK cytokines are involved in several different biological processes (Figure S5D). In line with the morphological and cellular changes supporting enhancement of EVT differentiation, genes involved in EMT (MCAM, TGFBR2, HEG1, VGLL3) [37][38][39][40] , cell invasion (ADGRE5, MMP11, TIMP3, S100P) [41][42][43] , and fusion (CD9, ADAM12) [44][45][46] are up-regulated by uNK cytokines (Figures 4A and S5D).…”