Mitotic spindle-organizing protein 2A (MZT2A) promotes cisplatin resistance through NEMO ubiquitination and NF-κB...

Lung adenocarcinoma (LUAD), as a highly malignant tumor, remains challenging because of resistance to chemotherapeutic agents. This study aims to elucidate the regulatory mechanism of mitotic spindle-organizing protein 2A (MZT2A) in chemotherapy resistance in LUAD to identify novel therapeutic targets. We analyzed the expression of MZT2A in LUAD cells/tissues and determined its relationship with hypoxia. We used flow cytometry and cell cisplatin resistance experiments to investigate the role of MZT2A in the apoptosis and chemoresistance of LUAD cells in vitro and in vivo. In addition, the mechanistic interaction between MZT2A, NF-κB essential modulator (NEMO), and OTU deubiquitinase with linear linkage specificity (OTULIN) was explored using coimmunoprecipitation, glutathione-S-transferase pull down, ubiquitination immunoprecipitation assay, and mutational analysis. The results indicated that MZT2A was positively correlated with hypoxia-inducible factor-1 alpha (HIF-1α) and was upregulated in human LUAD, especially in neoadjuvant-resistant tumors. It was also correlated with an advanced disease stage and poor survival. It suppressed apoptosis and promoted cisplatin resistance in vitro and in vivo. Mechanistically, MZT2A protected NEMO against deubiquitination by binding to the catalytic domain of OTULIN, which activated the NF-κB signaling pathway. These findings suggest that MZT2A can promote chemoresistance in human LUAD by activating the NF-κB signaling pathway. Importantly, we identified a novel mechanism for hypoxia-induced NF-κB that involves the HIF-1α-MTZ2A-OTULIN-NEMO signaling cascade. The study shed new light on the crosstalk between HIF-1α and NF-κB that drives tumor drug resistance. Here, we showed that MZT2A can serve as a therapeutic target for overcoming drug resistance in LUAD.