Positive TAZ-TDG feedback loop drives proneural-to-mesenchymal transition to promote glioblastoma progression

Glioblastoma multiforme (GBM) is the most prevalent malignant tumor of the central nervous system, featuring high heterogeneity and invasiveness. Proneural-mesenchymal transition (PMT) has garnered extensive attention as a crucial driving mechanism for glioblastoma invasion and progression; however, its molecular regulatory network remains ill-defined.

The expression and prognostic significance of TAZ were analyzed using bioinformatics tools. The function of TAZ was evaluated using in vitro and in vivo experiments. MeDIP and McrBC analyses were used to investigate the effect of TDG on methylation levels in the WWTR1 promoter region. ChIP-qPCR and Luciferase reporter assays were used to evaluate the binding affinity of TEAD4 to the TDG promoter.

Aberrantly expressed TAZ promotes PMT in GBM cells. Mechanistically, the high expression of TAZ is caused by thymine DNA glycosylase (TDG), which maintains the low methylation state of its promoter region. TDG is transcriptionally regulated by TAZ-TEAD4, forming a TAZ-TDG positive feedback loop that promotes PMT. Importantly, we confirmed the significant inhibitory effect of dual targeting of TAZ and TDG, both in vitro and in vivo.

Our data strongly indicate that the self-amplifying TDG-TAZ loop represents a previously unrecognized key participant in the progression of glioblastoma (GBM) via PMT, suggesting that TAZ and TDG may serve as potential therapeutic targets for GBM.