Zujue Cheng

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.

The proneural-to-mesenchymal transition (PMT) is a pivotal process in glioblastoma (GBM), driving enhanced tumor aggressiveness, therapeutic resistance, and recurrence. HSPA5, a member of the heat shock protein 70 (HSP70) family, plays a crucial role in regulating and maintaining protein stability and function. Although HSPA5 is a recognized marker of poor prognosis in glioma, its underlying mechanistic function remains poorly defined. Here, we demonstrated that HSPA5 expression is highest in the mesenchymal (MES) subtype of GBM. The overexpression of HSPA5 in proneural (PN) cells induced PMT and promoted malignant phenotypes, whereas its knockdown in MES cells suppressed PMT and attenuated tumorigenicity. We further established that HSPA5 drives PMT by activating the YAP/TAZ pathway in vitro and in vivo. The expression of MES markers CD44 and c-MET was transcriptionally regulated by YAP/TAZ. Mechanistically, HSPA5 interacts directly with YAP/TAZ, disrupting their association with β-TrCP. This protective interaction inhibits the ubiquitination and proteasomal degradation of YAP/TAZ. Furthermore, HSPA5 expression was positively correlated with YAP and TAZ levels across GBM subtypes. Patients with high expression of HSPA5, YAP, and TAZ exhibited significantly poorer overall survival. Collectively, our findings suggested that HSPA5 promotes PMT through the stabilization of YAP/TAZ and identified HSPA5 as a promising therapeutic target for GBM patients.

Invasive pituitary neuroendocrine tumors (PitNETs) are the most prevalent types of intracranial and neuroendocrine tumors. Their aggressive growth and difficulty in complete resection result in a high recurrence rate. Cystine transporter solute carrier family 7 member 11 (SLC7A11) is overexpressed in various cancers, which contributes to tumor growth, progression, and metastasis by promoting cystine uptake and glutathione biosynthesis. We identified SLC7A11 as an invasive biomarker based on three Gene Expression Omnibus cohorts. This study aimed to investigate the role of SLC7A11 in invasive PitNETs. Cell proliferation was assessed using CCK-8 and colony formation assays, while cell apoptosis was estimated with flow cytometry. Wound healing assays and transwell assays were utilized to evaluate migration and invasion ability. Our findings demonstrated that SLC7A11 was markedly upregulated in invasive PitNETs, and was associated with the invasiveness of PitNETs. Knockdown of SLC7A11 could largely suppress tumor cell proliferation, migration, and invasion, while inducing apoptosis. Furthermore, SLC7A11 depletion was implicated in regulating epithelial–mesenchymal transition and inactivating the PI3K/AKT signaling pathway. These insights suggest SLC7A11 as a potential therapeutic target for invasive PitNETs.