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

Since nuclear factor (NF) κB 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-κB in colorectal cancer (CRC). High expression of ARMC4 downregulated the expression of NF-κB-dependent genes, dramatically reduced NF-κB 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-κB. 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-κB negative regulator, thus uncovering ARMC4 as a potential new therapeutic target in CRC.