鉴定锌指 MIZ 型蛋白 2 作为一种癌蛋白，可增强 NAD 依赖性蛋白去乙酰化酶 Sirtuin-1 的去乙酰化酶活性，从而调节非小细胞肺癌中的 Wnt 和 Hippo 通路。
Identification of zinc finger MIZ-type containing 2 as an oncoprotein enhancing NAD-dependent protein deacetylase sirtuin-1 deacetylase activity to regulate Wnt and Hippo pathways in non-small-cell lung cancer.
机构信息
Department of Pathology, Shenbei New Area, College of Basic Medical Sciences and the First Hospital of China Medical University. No, 77 Puhe Road, Shenyang, 110122, Liaoning Province, People's Republic of China.
Department of Surgical Oncology and Breast Surgery, the First Hospital of China Medical University, Shenyang. No. 155 Nanjing North Street, Heping Area, Shenyang, 110001, Liaoning Province, People's Republic of China.
出版信息
Cell Mol Biol Lett. 2024 Sep 12;29(1):122. doi: 10.1186/s11658-024-00636-z.
BACKGROUND
Zinc finger MIZ-type containing 2 (ZMIZ2) can function as a coactivator and participate in the progression of certain malignant tumors; however, its expression and underlying molecular mechanism in non-small-cell lung cancer (NSCLC) remains unknown. In this study, we aim to analyze the expression of ZMIZ2 and its tumorigenic function in NSCLC, identifying its related factors.
METHODS
ZMIZ2 expression in NSCLC tissue samples and cell lines was examined using immunohistochemistry and western blotting; its biological role was investigated using in vivo and in vitro assays. The association between ZMIZ2 and NAD-dependent protein deacetylase sirtuin-1 (SIRT1) was demonstrated using mass spectrometry and immunoprecipitation experiments. Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG)-based enrichment analysis, luciferase reporter assay, and real-time quantitative polymerase chain reaction (RT-qPCR) were conducted to verify the impact of ZMIZ2-SIRT1 combination on Hippo/Wnt pathways.
RESULTS
ZMIZ2 was highly expressed in NSCLC and positively associated with advanced pTNM staging, lymph node metastasis, and poor overall survival. Functional experiments revealed that ZMIZ2 promotes the proliferation, migration, and invasiveness of lung cancer cells-establishing its role as a promoter of oncogenes. Molecular mechanism studies identified SIRT1 as an assisted key factor interacting with ZMIZ2. KEGG enrichment analysis revealed that ZMIZ2 is closely related to Wnt/Hippo pathways; ZMIZ2-SIRT1 interaction enhanced SIRT1 deacetylase activity. Direct downregulation of intranuclear β-catenin and yes-associated protein (YAP) acetylation levels occurred independently of upstream proteins in Wnt/Hippo pathways; transcriptional activities of β-catenin-transcription factor 4 (TCF4) and YAP-TEA domain family transcription factors (TEADs) were amplified.
CONCLUSIONS
ZMIZ2 promotes the malignant phenotype of lung cancer by regulating Wnt/Hippo pathways through SIRT1, providing an experimental basis for discovering novel biomarkers and developing tumor-targeted drugs.
背景
锌指 MIZ 型含 2 型（ZMIZ2）可作为共激活因子发挥作用，并参与某些恶性肿瘤的进展；然而，其在非小细胞肺癌（NSCLC）中的表达及其潜在的分子机制尚不清楚。在本研究中，我们旨在分析 ZMIZ2 在 NSCLC 中的表达及其致瘤功能，并确定其相关因素。
方法
采用免疫组织化学和 Western blot 检测 NSCLC 组织样本和细胞系中 ZMIZ2 的表达；通过体内和体外实验研究其生物学作用。采用质谱和免疫沉淀实验证实 ZMIZ2 与 NAD 依赖性蛋白去乙酰化酶 Sirtuin-1（SIRT1）之间的关联。采用京都基因与基因组百科全书（KEGG）通路富集分析、荧光素酶报告基因检测和实时定量聚合酶链反应（RT-qPCR）验证 ZMIZ2-SIRT1 组合对 Hippo/Wnt 通路的影响。
结果
ZMIZ2 在 NSCLC 中高表达，并与晚期 pTNM 分期、淋巴结转移和不良总生存期呈正相关。功能实验表明，ZMIZ2 促进肺癌细胞的增殖、迁移和侵袭，从而确立其作为癌基因促进子的作用。分子机制研究确定 SIRT1 是与 ZMIZ2 相互作用的辅助关键因子。KEGG 富集分析表明，ZMIZ2 与 Wnt/Hippo 通路密切相关；ZMIZ2-SIRT1 相互作用增强了 SIRT1 的去乙酰化酶活性。Wnt/Hippo 通路中的上游蛋白独立地降低了细胞核内β-连环蛋白和 yes 相关蛋白（YAP）的乙酰化水平；β-连环蛋白转录因子 4（TCF4）和 YAP-TEA 结构域家族转录因子（TEADs）的转录活性被放大。
结论
ZMIZ2 通过 SIRT1 调节 Wnt/Hippo 通路促进肺癌的恶性表型，为发现新的生物标志物和开发肿瘤靶向药物提供了实验依据。
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