SENP7 Mediates Desumoylation and Deubiquitination of SP1 to Promote Lung Adenocarcinoma Progression and Chemoresistance

Background Lung adenocarcinoma (LUAD) represents a significant global health challenge due to its elevated morbidity and mortality rates. Despite advancements in LUAD therapies, there remains an imperative need for novel therapeutic targets for patients who exhibit unresponsiveness or resistance to existing treatment modalities. Methods To investigate the potential role of SENP7 in LUAD progression, we analyzed SENP7 expression levels in LUAD and normal lung tissues using data from the TCGA, GTEx, and CPTAC databases, supplemented by immunohistochemistry (IHC) staining and western blotting assays. Additionally, the effects of SENP7 and SP1 on LUAD progression were assessed through CCK-8 assays, colony formation assays, EDU incorporation assays, and tumor xenograft experiments. To elucidate the role of the SENP7-SP1 pathway in LUAD progression, we conducted ubiquitination assays, co-immunoprecipitation (Co-IP), SUMOylation assays, and western blotting analyses. Results In this study, we demonstrated that the SENP7 protein is markedly expressed in LUAD, with a strong correlation to disease progression and adverse patient prognoses. Our findings reveal that the depletion of SENP7 substantially impedes LUAD progression in both in vitro and in vivo models. Importantly, we identified SP1 as a bona fide target of SENP7, with SENP7-mediated deSUMOylation, deubiquitination, and stabilization of SP1 being essential for LUAD development and chemoresistance. Conclusions These results underscore the pivotal role of the SENP7-SP1 axis in promoting chemoresistance and disease progression in LUAD, thereby providing a foundation for potential therapeutic strategies in the management of advanced cancer.