NAC-1 controls cell growth and survival by repressing transcription of Gadd45GIP1, a candidate tumor suppressor

Cancer mortality and morbidity are primarily related to recurrent tumors, and characterization of recurrence-associated genes should illuminate fundamental properties of tumor progression and provide new therapeutic targets. We have previously identified NAC-1, a member of the BTB/POZ gene family and a transcription repressor, as a gene associated with recurrent ovarian carcinomas after chemotherapy. We further showed that homodimerization of NAC-1 proteins Is essential for tumor growth and survival. In this study, we applied serial analysis of gene expression and identified growth arrest and DNA-damage-inducible 45-gamma interacting protein (Gadd45GIPI) as one of the downstream genes negatively regulated by NAC-1. NAC-1 knockdown in both SKOV3 and HeLa cells that expressed abundant endogenous NAC-1 induced Gadd45GIP1 expression transcriptionally; on the other hand, engineered expression of NAC-1 in NAC-1-negative RUE and HEK293 cells suppressed endogenous Gadd45GIPI expression. In NAC-1-expressing tumor cells, induction of dominant negative NAC-1 conferred a growth-inhibitory effect that can be partially reversed by Gadd45GIPI knockdown. Induced Gadd45GIP1 expression resulted in growth arrest in SKOV3 and HeLa cells both in vitro and in vivo. In summary, NAC-1 contributes to tumor growth and survival by at least inhibiting Gadd45GIP1 expression, which has a tumor suppressor effect in cancer cells.