Targeting the ZNF‐148/miR‐335/SOD2 signaling cascade triggers oxidative stress‐mediated pyroptosis and suppresses breast cancer progression

Abstract

Abstract Background The implication of zinc finger protein 148 (ZNF‐148) in pathophysiology of most human cancers has been reported; however, the biological functions of ZNF‐148 in breast cancer remain unclear. This study sought to elucidate the potential molecular mechanism of ZNF‐148 on breast cancer pathology. Methods ZNF148 expression was tested in breast cancer tissues and cells. Then, cells were transfected with ZNF‐148 overexpression or downregulation vector, and the cell proliferation, pyroptosis, apoptosis, and reactive oxygen species (ROS) production were analyzed by MTT, western blot, flow cytometry, and immunofluorescence staining, respectively. Tumor‐bearing nude mouse was used to evaluate tumorigenesis of ZNF‐148. Mechanisms underpinning ZNF‐148 were examined using bioinformatics and luciferase assays. Results We found that ZNF‐148 was upregulated in breast cancer tissues and cell lines. Knockdown of ZNF‐148 suppressed malignant phenotypes, including cell proliferation, epithelial‐mesenchymal transition, and tumorigenesis in vitro and in vivo, while ZNF‐148 overexpression had the opposite effects. Further experiments showed that ZNF‐148 deficiency promoted ROS production and triggered both apoptotic and pyroptotic cell death, which were restored by cotreating cells with ROS scavengers. A luciferase reporter assay revealed that miR‐335 was the downstream target of ZNF‐148 and that overexpressed ZNF‐148 increased superoxide dismutase 2 (SOD2) expression by sponging miR‐335. In parallel, both miR‐335 downregulation and SOD2 overexpression abrogated the antitumor effects of ZNF‐148 deficiency on proliferation and pyroptosis in breast cancer cells. Conclusions Our findings indicated that ZNF‐148 promotes breast cancer progression by triggering miR‐335/SOD2/ROS‐mediated pyroptotic cell death and aid the identification of potential therapeutic targets for breast cancer.

Keywords

• breast cancer
• miR‐335
• oxidative stress
• pyroptosis
• zinc finger protein 148