NKX3.1 stabilizes p53, inhibits AKT activation, and blocks prostate cancer initiation caused by PTEN loss
NKX3.1 stabilizes p53, inhibits AKT activation, and blocks prostate cancer initiation caused by PTEN loss
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DOI：
10.1016/j.ccr.2006.03.031
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发表时间：
2006-05-01
期刊：
影响因子：
50.3
通讯作者：
Wu, Hong
中科院分区：
文献类型：
--
作者：
Lei, Qunying;Jiao, Jing;Wu, Hong
我们证明，在小鼠和人类前列腺癌中，PTEN缺失都会导致NKX3.1表达降低。在Pten缺失的上皮细胞中体内恢复Nkx3.1表达会导致细胞增殖减少、细胞死亡增加以及肿瘤发生受到抑制。雄激素受体（AR）正向调节NKX3.1的表达，而NKX3.1负向调节AR转录，进而调节与AR相关的信号事件。与它的肿瘤抑制功能一致，NKX3.1通过与HDAC1结合作用于细胞周期和细胞死亡机制，通过MDM2依赖的机制导致p53乙酰化增加和半衰期延长。重要的是，Nkx3.1的过表达对Pten野生型上皮细胞影响很小，这表明PTEN在PTEN - NKX3.1的相互作用中起主要作用。调控NKX3.1的表达可能作为治疗PTEN缺陷型前列腺癌的一种治疗策略。
We demonstrate that PTEN loss causes reduced NKX3.1 expression in both murine and human prostate cancers. Restoration of Nkx3.1 expression in vivo in Pten null epithelium leads to decreased cell proliferation, increased cell death, and prevention of tumor initiation. Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events. Consistent with its tumor suppressor functions, NKX3.1 engages cell cycle and cell death machinery via association with HDAC1, leading to increased p53 acetylation and half-life through MDM2-dependent mechanisms. Importantly, overexpression of Nkx3.1 has little effect on Pten wild-type epithelium, suggesting that PTEN plays a predominant role in PTEN-NKX3.1 interplay. Manipulating NKX3.1 expression may serve as a therapeutic strategy for treating PTEN-deficient prostate cancers.