| First Author | El-Nikhely N | Year | 2020 |
| Journal | Cancer Res | Volume | 80 |
| Issue | 19 | Pages | 4199-4211 |
| PubMed ID | 32816854 | Mgi Jnum | J:296659 |
| Mgi Id | MGI:6467625 | Doi | 10.1158/0008-5472.CAN-20-1158 |
| Citation | El-Nikhely N, et al. (2020) Metastasis-Associated Protein 2 Represses NF-kappaB to Reduce Lung Tumor Growth and Inflammation. Cancer Res 80(19):4199-4211 |
| abstractText | Although NF-kappaB is known to play a pivotal role in lung cancer, contributing to tumor growth, microenvironmental changes, and metastasis, the epigenetic regulation of NF-kappaB in tumor context is largely unknown. Here we report that the IKK2/NF-kappaB 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-kappaB signaling and tumor growth, whereas later dissociation of MTA2/NuRD complex from the promoter of NF-kappaB target genes and IKK2-dependent positive regulation of MTA2 leads to activation of NF-kappaB signaling, epithelial-mesenchymal transition, and lung tumor metastasis. These findings reveal a previously unrecognized biphasic role of MTA2 in IKK2/NF-kappaB-driven primary-to-metastatic lung tumor progression. Addressing the interaction between MTA2 and NF-kappaB 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-kappaB signaling modulatory functions. |
