Background: TGF-β-induced factor homeobox 2 (TGIF2) is a transcription regulator that is phosphorylated by EGFR/ERK signaling. However, the functions of phosphorylated (p)-TGIF2 in cancer are largely unknown. Here, we investigated the roles of p-TGIF2 in promoting epithelial-mesenchymal transition (EMT) and metastasis in lung adenocarcinoma (LUAD).
Methods: In vitro and in vivo experiments were conducted to investigate the role of TGIF2 in LUAD EMT and metastasis. Dual-luciferase reporter and ChIP assays were employed to observe the direct transcriptional regulation of E-cadherin by TGIF2 and HDAC1. Co-immunoprecipitation was performed to identify the interaction between TGIF2 and HDAC1.
Results: Downregulating the expression of TGIF2 inhibited LUAD cell migration, EMT and metastasis in vitro and in vivo. Phosphorylation of TGIF2 by EGFR/ERK signaling was required for TGIF2-promoted LUAD EMT and metastasis since phosphorylation-deficient TGIF2 mutant lost these functions. Phosphorylation of TGIF2 was necessary to recruit HDAC1 to the E-cadherin promoter sequence and subsequently suppress E-cadherin transcription. Meanwhile, inhibition of HDAC1 repressed the TGIF2 phosphorylation-induced migration and EMT of LUAD cells. In xenograft mouse models, both inhibition of ERK and HDAC1 could significantly inhibited TGIF2-enhanced metastasis. Furthermore, TGIF2-positive staining was significantly correlated with E-cadherin-negative staining in human lung cancer specimens.
Conclusions: Our study reveals the novel function of p-TGIF2 in promoting EMT and metastasis in LUAD; p-TGIF2 could be a potential therapeutic target to inhibit LUAD metastasis.
Keywords: E-cadherin; EMT; HDAC1; Lung adenocarcinoma; p-TGIF2.
© 2023. The Author(s).