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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.