Metastasis-associated protein 2 represses NF-kB to reduce lung tumor growth and inflammation

Abstract

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