NAC-1 controls cell growth and survival by repressing transcription of Gadd45GIP1, a candidate tumor suppressor
NAC-1 controls cell growth and survival by repressing transcription of Gadd45GIP1, a candidate tumor suppressor
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DOI：
10.1158/0008-5472.can-07-1357
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发表时间：
2007-09-01
期刊：
影响因子：
11.2
通讯作者：
Shih, Ie-Ming
中科院分区：
文献类型：
--
作者：
Nakayama, Kentaro;Nakayama, Naomi;Shih, Ie-Ming
癌症的死亡率和发病率主要与肿瘤复发相关，对复发相关基因的特征描述应能阐明肿瘤进展的基本特性，并提供新的治疗靶点。我们先前已鉴定出NAC - 1，它是BTB/POZ基因家族的成员以及一种转录抑制因子，是与化疗后复发性卵巢癌相关的基因。我们进一步表明，NAC - 1蛋白的同源二聚化对肿瘤生长和存活至关重要。在这项研究中，我们应用基因表达系列分析，鉴定出生长停滞和DNA损伤诱导蛋白45 - γ相互作用蛋白（Gadd45GIP1）是受NAC - 1负调控的下游基因之一。在表达大量内源性NAC - 1的SKOV3和HeLa细胞中，敲低NAC - 1可在转录水平上诱导Gadd45GIP1的表达；另一方面，在NAC - 1阴性的RUE和HEK293细胞中，人为表达NAC - 1会抑制内源性Gadd45GIP1的表达。在表达NAC - 1的肿瘤细胞中，诱导显性负性NAC - 1会产生生长抑制作用，这种作用可通过敲低Gadd45GIP1而部分逆转。诱导的Gadd45GIP1表达在体外和体内都导致SKOV3和HeLa细胞的生长停滞。总之，NAC - 1至少通过抑制Gadd45GIP1的表达来促进肿瘤生长和存活，而Gadd45GIP1在癌细胞中具有肿瘤抑制作用。
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.