Metastasis-Associated Protein 2 Represses NF-κB to Reduce Lung Tumor Growth and Inflammation.
Fiche publication
Date publication
octobre 2020
Journal
Cancer research
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BARRETO Guillermo
Tous les auteurs :
El-Nikhely N, Karger A, Sarode P, Singh I, Weigert A, Wietelmann A, Stiewe T, Dammann R, Fink L, Grimminger F, Barreto G, Seeger W, Pullamsetti SS, Rapp UR, Savai R
Lien Pubmed
Résumé
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.
Mots clés
Animals, Cell Line, Tumor, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, HEK293 Cells, Histone Deacetylases, genetics, Humans, I-kappa B Kinase, genetics, Inflammation, pathology, Lung Neoplasms, genetics, Mice, Inbred C57BL, Mice, Transgenic, NF-kappa B, genetics, Repressor Proteins, genetics, Signal Transduction, Trans-Activators, genetics, Tumor Microenvironment
Référence
Cancer Res. 2020 10 1;80(19):4199-4211