SENP1 inhibition suppresses the growth of lung cancer cells through activation of A20-mediated ferroptosis

Background: Ferroptosis is a type of cell death driven by iron accumulation and lipid peroxidation, which is involved in the pathogenesis of various tumors. Small ubiquitin-like modifier (SUMO)-specific protease 1 (SENP1) is a critical SUMO-specific protease, which controls multiple cellular signaling processes. However, the roles and mechanisms of SENP1-mediated protein SUMOylation in the regulation of cell death and ferroptosis remain unexplored. Methods: The gene expression of SENP1 and ferroptosis-related genes in samples of lung cancer patient and cells were determined by immunohistochemical staining, real-time polymerase chain reaction (RT-qPCR) and Western blot. The association of gene expression with the survival rate of lung cancer patients was analyzed from public database. The erastin and cisplatin was used to induce ferroptosis, and cell ferroptosis were determined by evaluated lipid-reactive oxygen species (ROS), cell viability and electron microscopy. The protein interaction was determined by immunoprecipitation (IP) and shotgun proteomics analysis. An in vivo tumor transplantation model of immunodeficient mice was used to evaluate the effect of SENP1 on tumor growth in vivo. Results: SENP1 is aberrantly overexpressed in lung cancer cells and is associated with the low survival rate of patients. SENP1 inhibition by short hairpin RNA transduction or a specific inhibitor suppressed the proliferation and growth of lung cancer cells both in vitro and in vivo. SENP1 overexpression protected lung cancer cells from ferroptosis induced by erastin or cisplatin. Transcriptome and proteomics profiles revealed the involvement of SUMOylation regulation of the inflammation signal A20 in SENP1 inhibition-induced ferroptosis. Functional studies proved that A20 functions as a positive inducer and enhances the ferroptosis of A549 cells. A20 was shown to interact with ACSL4 and SLC7A11 to regulate the ferroptosis of lung cancer cells. Conclusions: SENP1 was identified as a suppressor of ferroptosis through a novel network of A20 SUMOylation links ACSL4 and SLC7A11 in lung cancer cells. SENP1 inhibition promotes ferroptosis and apoptosis and represents a novel therapeutic target for lung cancer therapy.