TFAP2C Affects PI3K/AKT/mTOR Pathway-Mediated EMT for Glioblastoma Development Through Transcriptional Regulation

Transcription factor AP-2 gamma (TFAP2C) plays a pro-cancer role in various malignancies. Yet, the action of TFAP2C in glioblastoma (GBM) is unknown. This study aimed to investigate the effects of TFAP2C in GBM and the potential mechanism. TFAP2C knockdown in GBM cell lines was employed to examine its impact on cell proliferation, migration, and invasion (PMI), as well as epithelial-mesenchymal transition (EMT) development, and its association with the PI3K/Akt/mTOR (PAM) pathway by co-overexpressing PI3K or SC79 treatment (Akt Agonist). The binding of TFAP2C and the PI3K promoter was predicted and validated. Finally, the above effects and mechanisms were verified in in vivo animal experiments. TFAP2C expression was strikingly heightened in human GBM cell lines and showed a negative correlation with patient survival. TFAP2C silencing inhibited GBM cell PMI, N-Cadherin and Vimentin expression, and the PAM pathway, and activated E-cadherin and ZO-1 expression. Overexpression of PI3K or SC79 treatment reversed the above changes, suggesting that TFAP2C promotes GBM cell PMI and EMT via the PAM pathway. Mechanistically, TFAP2C binds to the promoter of PI3K and regulates PI3K transcription. Finally, the in vitro results were further validated in animal experiments. In conclusion, TFAP2C promotes PI3K transcription through direct binding to the promoter of PI3K and activates the PAM pathway to promote GBM proliferation and EMT, providing a potential therapeutic target for GBM.

PI3K/AKT/mTOR (PAM) pathway; epithelial‐mesenchymal transition (EMT); glioblastoma; transcription factor AP‐2 gamma (TFAP2C); transcriptional regulation.