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

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-beta (TGF-beta)-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.