Using VBIM Technique to Discover ARMC4/ODAD2 as a Novel Negative Regulator of NF-kappa B and a New Tumor Suppressor in Colorectal Cancer

Since nuclear factor (NF) kappa B plays pivotal roles in inflammation and cancer, understanding its regulation holds great promise for disease therapy. Using the powerful validation-based insertional mutagenesis (VBIM) technique established by us previously, we discovered armadillo repeat-containing protein 4 (ARMC4)/outer dynein arm docking complex subunit 2 (ODAD2), a rarely studied protein known to date, as a novel negative regulator of NF-kappa B in colorectal cancer (CRC). High expression of ARMC4 downregulated the expression of NF-kappa B-dependent genes, dramatically reduced NF-kappa B activity, cellular proliferation, anchorage-independent growth, and migratory ability in vitro, and significantly decreased xenograft tumor growth in vivo. Co-immunoprecipitation experiments demonstrated that ARMC4 forms a complex with NF-kappa B. Importantly, the lower ARMC4 expression in patient tumors than normal tissues indicates its potential tumor suppressor function in CRC. Collectively, we uncovered a completely new facet of ARMC4 function by identifying it as a novel NF-kappa B negative regulator, thus uncovering ARMC4 as a potential new therapeutic target in CRC.