Abstract
Abstract
Purpose
Bladder cancer (BLCA) is one of the most common malignancies of the urinary tract and is characterized by high recurrence and progression rates. Although urinary ZNF154 hypermethylation has been associated with an increased risk of BLCA recurrence, the biological function and molecular mechanism of ZNF154 in BLCA remain unclear. Therefore, this study aimed to investigate the role of ZNF154 in ferroptosis and its underlying molecular mechanism in BLCA.
Methods
Bioinformatics, BLCA tissues, and cell lines were used to assess ZNF154 expression. Gain- and loss-of-function assays evaluated malignant phenotypes. Ferroptosis indicators and related proteins were measured. GSEA, RNA-seq, ChIP-qPCR, dual-luciferase reporter assays and rescue experiments were performed to investigate the involvement of the PTEN/PI3K/AKT axis. Xenograft models enabled in vivo validation.
Results
ZNF154 was downregulated in BLCA. ZNF154 overexpression suppressed bladder cancer cell proliferation by inducing ferroptosis, as evidenced by mitochondrial damage, increased lipid ROS and MDA levels, decreased GSH levels, and reduced SLC7A11 and GPX4 expression. Mechanistically, ZNF154 positively regulated PTEN transcription, thereby suppressing PI3K/AKT signaling. Rescue experiments further supported the involvement of the PTEN/PI3K/AKT pathway in ZNF154-mediated ferroptosis, and PI3K/AKT activation reversed the ferroptotic phenotype induced by ZNF154 overexpression. A T24 xenograft model further supported the tumor-suppressive effect of ZNF154 in vivo and was accompanied by changes in ferroptosis-related markers.
Conclusions
ZNF154 positively regulates PTEN transcription, thereby suppressing PI3K/AKT signaling, reducing SLC7A11 and GPX4 expression, and promoting ferroptosis. These findings suggest that ZNF154 may serve as a potential prognostic biomarker and therapeutic target for BLCA.