Liu Ping, Li Shangwei, Gan Lu, Kao Timothy P, Huang Haojie
Department of Laboratory Medicine and Pathology, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Cancer Res. 2008 Dec 15;68(24):10290-9. doi: 10.1158/0008-5472.CAN-08-2038.
Increasing evidence suggests that aberrant activation of the androgen receptor (AR) plays a pivotal role in the development and progression of androgen depletion-independent prostate cancer (PCa) after androgen deprivation therapy. Here, we show that loss of the PTEN tumor suppressor gene is associated with hyperactivation of the AR in human PCa cell lines. This effect is mediated primarily by its downstream effector FOXO1. In addition to the inhibition of androgenic activation of the AR, forced expression of FOXO1 in PTEN-negative PCa cells also inhibits androgen-independent activation of the AR in a manner independent of FOXO1 transcriptional function. In contrast, silencing of FOXO1 in PTEN-positive cells not only increases the basal activity of the AR in the absence of androgens, it also markedly sensitizes the AR activation by low levels of androgens or nonandrogenic factors such as interleukin-6. FOXO1-mediated inhibition of the AR is partially attenuated by the histone deacetylase (HDAC) inhibitor trichostatin A. Accordingly, FOXO1 interacts with HDAC3 as shown by coimmunoprecipitation assays, and cotransfection of cells with FOXO1 and HDAC3, but not HDAC1 and HDAC2, results in a greater inhibition of AR activity than in cells transfected with FOXO1 or HDAC3 individually. Together, our findings define a novel corepressor function of FOXO1 in inhibition of androgen-independent activation of the AR.
越来越多的证据表明，雄激素受体（AR）的异常激活在雄激素剥夺治疗后雄激素非依赖性前列腺癌（PCa）的发生和发展中起关键作用。在此，我们表明PTEN肿瘤抑制基因的缺失与人类PCa细胞系中AR的过度激活相关。这种效应主要由其下游效应因子FOXO1介导。除了抑制AR的雄激素激活外，在PTEN阴性的PCa细胞中强制表达FOXO1还以独立于FOXO1转录功能的方式抑制AR的雄激素非依赖性激活。相反，在PTEN阳性细胞中沉默FOXO1不仅会增加在无雄激素情况下AR的基础活性，还会显著增强低水平雄激素或白细胞介素-6等非雄激素因子对AR的激活作用。组蛋白去乙酰化酶（HDAC）抑制剂曲古抑菌素A可部分减弱FOXO1介导的对AR的抑制作用。因此，共免疫沉淀试验表明FOXO1与HDAC3相互作用，并且与单独转染FOXO1或HDAC3的细胞相比，将FOXO1和HDAC3共转染到细胞中对AR活性的抑制作用更强，而HDAC1和HDAC2则无此作用。总之，我们的研究结果确定了FOXO1在抑制AR雄激素非依赖性激活中的一种新的共抑制因子功能。
