COMMD1, from the Repair of DNA Double Strand Breaks, to a Novel Anti-Cancer Therapeutic Target

SIMPLE SUMMARY: Lung cancer is the most commonly diagnosed cancer worldwide and additionally the most common cause of death from cancer, with non-small cell lung cancers (NSCLC) being the most commonly diagnosed form of the disease. As drug resistance is a key issue halting chemotherapy effectiveness, there is a great need to identify new therapeutic targets. The aims of this study were to investigate the function of the protein, COMMD1, in the repair of DNA double strand breaks and the therapeutic potential of COMMD1 in NSCLC. Here, we demonstrate for the first time how an additional COMMD family member, COMMD1, functions in the repair of DNA double strand breaks and may be relevant as a therapeutic target and prognostic factor in NSCLC. These novel findings highlight the potential of a novel approach to NSCLC therapy, by targeting an overexpressed protein. ABSTRACT: Lung cancer has the highest incidence and mortality among all cancers, with non-small cell lung cancer (NSCLC) accounting for 85–90% of all lung cancers. Here we investigated the function of COMMD1 in the repair of DNA double strand breaks (DSBs) and as a prognostic and therapeutic target in NSCLC. COMMD1 function in DSB repair was investigated using reporter assays in COMMD1-siRNA-depleted cells. The role of COMMD1 in NSCLC was investigated using bioinformatic analysis, qRT-PCR and immunoblotting of control and NSCLC cells, tissue microarrays, cell viability and cell cycle experiments. DNA repair assays demonstrated that COMMD1 is required for the efficient repair of DSBs and reporter assays showed that COMMD1 functions in both non-homologous-end-joining and homologous recombination. Bioinformatic analysis showed that COMMD1 is upregulated in NSCLC, with high levels of COMMD1 associated with poor patient prognosis. COMMD1 mRNA and protein were upregulated across a panel of NSCLC cell lines and siRNA-mediated depletion of COMMD1 decreased cell proliferation and reduced cell viability of NSCLC, with enhanced death after exposure to DNA damaging-agents. Bioinformatic analyses demonstrated that COMMD1 levels positively correlate with the gene ontology DNA repair gene set enrichment signature in NSCLC. Taken together, COMMD1 functions in DSB repair, is a prognostic maker in NSCLC and is potentially a novel anti-cancer therapeutic target for NSCLC.