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

El-Nikhely, N., Karger, A., Sarode, P., Singh, I., Weigert, A., Wietelmann, A., et al. (2020). Metastasis-Associated Protein 2 Represses NF-kappa B to Reduce Lung Tumor Growth and Inflammation. CANCER RESEARCH, 80(19), 4199-4211. doi:10.1158/0008-5472.CAN-20-1158.

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El-Nikhely, Nefertiti1, Author           
Karger, Annika1, Author           
Sarode, Poonam1, Author           
Singh, Indrabahadur2, Author           
Weigert, Andreas, Author
Wietelmann, Astrid3, Author           
Stiewe, Thorsten, Author
Dammann, Reinhard, Author
Fink, Ludger, Author
Grimminger, Friedrich, Author
Barreto, Guillermo2, Author           
Seeger, Werner1, Author           
Pullamsetti, Soni S.1, Author           
Rapp, Ulf R.1, Author           
Savai, Rajkumar1, Author           
Affiliations:
1Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              
2Lung Cancer Epigenetics, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591699              
3Small Animal Magnetic Resonance Imaging, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591708              

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 Abstract: Although NF-kappa B is known to play a pivotal role in lung cancer, contributing to tumor growth, microenvironmental changes, and metastasis, the epigenetic regulation of NF-kappa B in tumor context is largely unknown. Here we report that the IKK2/NF-kappa B 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-kappa B signaling and tumor growth, whereas later dissociation of MTA2/NuRD complex from the promoter of NF-kappa B target genes and IKK2-dependent positive regulation of MTA2 leads to activation of NF-kappa B signaling, epithelial-mesenchymal transition, and lung tumor metastasis. These findings reveal a previously unrecognized biphasic role of MTA2 in IKK2/NF-kappa B-driven primary-to-metastatic lung tumor progression. Addressing the interaction between MTA2 and NF-kappa B 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-kappa B signaling modulatory functions.

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 Dates: 2020-08-142020
 Publication Status: Published in print
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Title: CANCER RESEARCH
Source Genre: Journal
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Pages: - Volume / Issue: 80 (19) Sequence Number: - Start / End Page: 4199 - 4211 Identifier: ISSN: 0008-5472