Abstract
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 (Gadd45GIP1) 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 RK3E and HEK293 cells suppressed endogenous Gadd45GIP1 expression. In NAC-1-expressing tumor cells, induction of dominant negative NAC-1 conferred a growth-inhibitory effect that can be partially reversed by Gadd45GIP1 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.
Highlights
The genes of the BTB/POZ family act as ubiquitous transcription repressors and participate in several cellular functions, including proliferation, apoptosis, transcription control, and cell morphology maintenance [1]
To elucidate the mechanisms underlying the effects of NAC-1 in promoting tumor growth and survival, we used the N130 dominant negative system because N130 was a truncated protein of NAC-1 containing only the BTB/POZ domain, and induction of N130 was shown to be more potent in inactivating NAC-1 than gene knockdown using small interfering RNA (siRNA) [15]
Using LongSAGE as a discovery tool and real-time PCR as a validation method, we identified and validated seven genes that were up-regulated after NAC-1 inactivation by the dominant negative NAC-1 (N130) but were unable to validate any genes that were down-regulated by NAC-1 inactivation, a finding consistent with transcription repressor roles of the BTB/POZ family members [23, 24]
Summary
The genes of the BTB/POZ family act as ubiquitous transcription repressors and participate in several cellular functions, including proliferation, apoptosis, transcription control, and cell morphology maintenance [1]. The roles of BTB/POZ proteins in human cancer have been recently revealed because several of the BTB/POZ proteins have been shown to be involved in cancer development, and they include. 8, 10), leukemia/lymphoma related factor (LRF)/Pokemon [11, 12], HIC-1 (hypermethylated in cancer-1), and Kaiso [13, 14]. Peptide inhibitors that block interaction between the BCL-6 BTB/POZ domain and its corepressor suppress BCL-6 oncogenic functions in neoplastic B lymphocytes, suggesting a potential of that peptide inhibitor of the BTB/POZ domain may provide a novel therapeutic agent for B-cell lymphoma [9]. LRF directly represses transcription of the tumor suppressor gene ARF, enhancing tumor development [11]
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