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

Autor:	El-Nikhely N; Max Planck Institute for Heart and Lung Research, German Center for Lung Research (DZL), Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany., Karger A; Max Planck Institute for Heart and Lung Research, German Center for Lung Research (DZL), Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany., Sarode P; Max Planck Institute for Heart and Lung Research, German Center for Lung Research (DZL), Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany., Singh I; Max Planck Institute for Heart and Lung Research, German Center for Lung Research (DZL), Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany., Weigert A; Institute of Biochemistry I, Goethe University Frankfurt, Frankfurt, Germany., Wietelmann A; Max Planck Institute for Heart and Lung Research, German Center for Lung Research (DZL), Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany., Stiewe T; Institute of Molecular Oncology, German Center for Lung Research (DZL), Philipps-University Marburg, Marburg, Germany., Dammann R; Institute for Genetics; member of the German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany., Fink L; Institute of Pathology and Cytology, UEGP, Wetzlar, Germany., Grimminger F; Department of Internal Medicine, German Center for Lung Research (DZL), Cardio-Pulmonary Institute (CPI), Justus Liebig University, Giessen, Germany., Barreto G; Institute of Molecular Oncology, German Center for Lung Research (DZL), Philipps-University Marburg, Marburg, Germany.; Brain and Lung Epigenetics (BLUE), Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Université Paris-Est Créteil (UPEC), Créteil, France., Seeger W; Max Planck Institute for Heart and Lung Research, German Center for Lung Research (DZL), Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany.; Department of Internal Medicine, German Center for Lung Research (DZL), Cardio-Pulmonary Institute (CPI), Justus Liebig University, Giessen, Germany.; Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany., Pullamsetti SS; Max Planck Institute for Heart and Lung Research, German Center for Lung Research (DZL), Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany.; Department of Internal Medicine, German Center for Lung Research (DZL), Cardio-Pulmonary Institute (CPI), Justus Liebig University, Giessen, Germany., Rapp UR; Max Planck Institute for Heart and Lung Research, German Center for Lung Research (DZL), Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany., Savai R; Max Planck Institute for Heart and Lung Research, German Center for Lung Research (DZL), Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany. rajkumar.savai@mpi-bn.mpg.de.; Department of Internal Medicine, German Center for Lung Research (DZL), Cardio-Pulmonary Institute (CPI), Justus Liebig University, Giessen, Germany.; Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2020 Oct 01; Vol. 80 (19), pp. 4199-4211. Date of Electronic Publication: 2020 Aug 14.
DOI:	10.1158/0008-5472.CAN-20-1158
Abstrakt:	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. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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