Regulation of the tumor suppressor FOXO3 by the thromboxane-A2 receptors in urothelial cancer.
Regulation of the tumor suppressor FOXO3 by the thromboxane-A2 receptors in urothelial cancer.
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DOI：
10.1371/journal.pone.0107530
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Moussa O
中科院分区：
文献类型：
--
作者：
Sobolesky PM;Halushka PV;Garrett-Mayer E;Smith MT;Moussa O
转录因子FOX03是一种成熟的肿瘤抑制因子，其活性、稳定性和定位都受磷酸化和乙酰化的调节。我们实验室以前的数据表明，扩增的血栓烷-A2信号与膀胱癌患者的不良预后和体内血栓素-A2异构体-β受体(TPβ)的过度表达有关，但与TPα诱导的永生化膀胱细胞恶性转化无关。在此，我们描述了TP通过磷酸化和脱乙酰化在膀胱癌细胞模型中调节FOXO_3活性和定位的机制。在未转化的细胞系UROsta和SV-Huc中进行的体外功能获得和丧失研究表明，shRNA下调FOXO_3的表达增加了细胞的迁移和侵袭，而外源过表达TPβ则提高了基础磷酸化(P)FOXO_3-S294的水平。相反，过表达ERK抗性的突变型FOXO3可减少UMUC3细胞迁移和侵袭的增加，包括TP激动剂(U46619)介导的迁移和侵袭。此外，用U46619刺激UMUC3细胞可增加pFOX03-S294的表达，这种作用可被TP拮抗剂(PTXA2)或ERK抑制剂(U0126)所减弱。最初，U46619引起pFOXO_3-S294的胞核聚集；然而，长时间的刺激增加了FOXO_3的胞浆定位。U46619刺激降低了FOXO3的整体转录活性，但与其促生存靶标--锰超氧化物歧化酶的表达增加有关。数据还显示，TP刺激增加了组蛋白脱乙酰酶SIRT1的表达，并与乙酰化FOXO_3的减少相对应。总而言之，这些数据表明，TP信号在FOXO_3活性的调节中发挥作用，部分是通过磷酸化和脱乙酰化来调节的。
The transcription factor FOXO3 is a well-established tumor suppressor whose activity, stability, and localization are regulated by phosphorylation and acetylation. Previous data by our laboratory demonstrated amplified thromboxane-A2 signaling was associated with poor prognoses in bladder cancer patients and overexpression of the thromboxane-A2 isoform-β receptor (TPβ), but not TPα, induced malignant transformation of immortalized bladder cells in vivo. Here, we describe a mechanism of TP mediated modulation of FOXO3 activity and localization by phosphorylation and deacetylation in a bladder cancer cell model. In vitro gain and loss of function studies performed in non-transformed cell lines, UROsta and SV-HUC, revealed knockdown of FOXO3 expression by shRNA increased cell migration and invasion, while exogenously overexpressing TPβ raised basal phosphorylated (p)FOXO3-S294 levels. Conversely, overexpression of ERK-resistant, mutant FOXO3 reduced increases in UMUC3 cell migration and invasion, including that mediated by TP agonist (U46619). Additionally, stimulation of UMUC3 cells with U46619 increased pFOXO3-S294 expression, which could be attenuated by treatment with a TP antagonist (PTXA2) or ERK inhibitor (U0126). Initially U46619 caused nuclear accumulation of pFOXO3-S294; however, prolonged stimulation increased FOXO3 cytoplasmic localization. U46619 stimulation decreased overall FOXO3 transcriptional activity, but was associated with increased expression of its pro-survival target, manganese superoxide dismutase. The data also shows that TP stimulation increased the expression of the histone deacetylase, SIRT1, and corresponded with decreased acetylated-FOXO3. Collectively, the data suggest a role for TP signaling in the regulation of FOXO3 activity, mediated in part through phosphorylation and deacetylation.
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