Identification of ZMIZ2 as a co-activator enhancing SIRT1 deacetylase activity in regulating Wnt and Hippo signalling pathways

Abstract Zinc finger MIZ-type containing 2 (ZMIZ2) is recognized as a ‘co-activator’ involved in embryonic development and the progression of certain malignant tumours. However, its expression and molecular mechanism in non-small cell lung cancer remain inadequately understood. Additionally, the relevant “assisted factors” of ZMIZ2 remain incompletely identified. Therefore, this study aims to investigate ZMIZ2 expression in non-small cell lung cancer tissue samples and cell lines through immunohistochemistry and immunoblotting. The goal is to establish its correlation with advanced pTNM staging, lymph node metastasis, and poor prognosis. Several in vivo and in vitro functional experiments have consistently shown that the introduction of ZMIZ2 promotes the proliferation, migration, and invasiveness of lung cancer cells, thus establishing its role as a promoter of oncogenes. Investigating the molecular mechanism, we applied mass spectrometry analysis and immunoprecipitation experiments, leading to the identification of the deacetylase Sirtuin 1 (SIRT1) as an ‘assisted key factor’ capable of interacting with ZMIZ2. Furthermore, KEGG enrichment analysis suggests that ZMIZ2 is closely related to the Wnt and Hippo pathways. Furthermore, we validated that the interaction between ZMIZ2 and SIRT1 enhances SIRT1 deacetylase activity. This direct downregulation of intranuclear β-catenin and YAP acetylation levels occurs independently of upstream proteins in the Wnt/Hippo pathways. It amplifies β-catenin-TCF4 and YAP-TEAD transcriptional activities, thereby regulating the Wnt and Hippo pathway. This results in the malignant transformation of lung cancer cells, providing a relevant experimental basis for searching for new biomarkers and the development of tumour-targeted medications.