Tumor and Stem Cell Biology Dysfunction of Nucleus Accumbens-1 Activates Cellular Senescence and Inhibits Tumor Cell Proliferation and Oncogenesis

Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the BTB/POZ gene family, has emerging roles in cancer. We report here that NAC1 acts as a negative regulator of cellular senescence in transformed and nontransformed cells, and dysfunction ofNAC1 induces senescence and inhibits its oncogenic potential.We show that NAC1 deficiency markedly activates senescence and inhibits proliferation in tumor cells treated with sublethal doses of g-irradiation. In mouse embryonic fibroblasts from NAC1 knockout mice, following infection with a Ras virus, NAC1 / cells undergo significantly more senescence and are either nontransformed or less transformed in vitro and less tumorigenic in vivowhen compared with NAC1þ/þ cells. Furthermore, we show that the NAC1-caused senescence blunting is mediated by DNp63, which exerts its effect on senescence through p21, and that NAC1 activates transcription of DNp63 under stressful conditions. Our results not only reveal a previously unrecognized function of NAC1, the molecular pathway involved and its impact on pathogenesis of tumor initiation and development, but also identify a novel senescence regulator that may be exploited as a potential target for cancer prevention and treatment. Cancer Res; 72(16); 4262–75. 2012 AACR.