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Metastasis-Associated Protein 2 Represses NF-κB to Reduce Lung Tumor Growth and Inflammation

2020; American Association for Cancer Research; Volume: 80; Issue: 19 Linguagem: Inglês

10.1158/0008-5472.can-20-1158

1538-7445

Nefertiti El-Nikhely, Annika Karger, Poonam Sarode, Indrabahadur Singh, Andreas Weigert, Astrid Wietelmann, Thorsten Stiewe, Reinhard Dammann, Ludger Fink, Friedrich Grimminger, Guillermo Barreto, Werner Seeger, Soni Savai Pullamsetti, Ulf R. Rapp, Rajkumar Savai,

Peptidase Inhibition and Analysis

Abstract Although NF-κB is known to play a pivotal role in lung cancer, contributing to tumor growth, microenvironmental changes, and metastasis, the epigenetic regulation of NF-κB in tumor context is largely unknown. Here we report that the IKK2/NF-κB signaling pathway modulates metastasis-associated protein 2 (MTA2), a component of the nucleosome remodeling and deacetylase complex (NuRD). In triple transgenic mice, downregulation of IKK2 (Sftpc-cRaf-IKK2DN) in cRaf-induced tumors in alveolar epithelial type II cells restricted tumor formation, whereas activation of IKK2 (Sftpc-cRaf-IKK2CA) supported tumor growth; both effects were accompanied by altered expression of MTA2. Further studies employing genetic inhibition of MTA2 suggested that in primary tumor growth, independent of IKK2, MTA2/NuRD corepressor complex negatively regulates NF-κB signaling and tumor growth, whereas later dissociation of MTA2/NuRD complex from the promoter of NF-κB target genes and IKK2-dependent positive regulation of MTA2 leads to activation of NF-κB signaling, epithelial–mesenchymal transition, and lung tumor metastasis. These findings reveal a previously unrecognized biphasic role of MTA2 in IKK2/NF-κB-driven primary-to-metastatic lung tumor progression. Addressing the interaction between MTA2 and NF-κB would provide potential targets for intervention of tumor growth and metastasis. Significance: These findings strongly suggest a prominent role of MTA2 in primary tumor growth, lung metastasis, and NF-κB signaling modulatory functions.