Unveiling the Association of STAT3 and HO-1 in Prostate Cancer: Role beyond Heme Degradation
Unveiling the Association of STAT3 and HO-1 in Prostate Cancer: Role beyond Heme Degradation
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DOI：
10.1593/neo.121358
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发表时间：
2012-11-01
期刊：
影响因子：
4.8
通讯作者：
Vazquez, Elba
中科院分区：
文献类型：
--
作者：
Elguero, Belen;Gueron, Geraldine;Vazquez, Elba
雄激素受体（AR）的激活是前列腺癌（PCa）发展的关键步骤。在AR激活中已经确定了几种机制，其中包括信号转导子和转录激活子3（STAT 3）信号转导。STAT 3活性的破坏与癌症进展相关。最近的研究表明，血红素加氧酶1（HO-1）可能在PCa中发挥关键作用，可能是独立于其催化功能。我们试图探索HO-1是否通过STAT 3轴对AR转录活性起作用。我们的研究结果表明，HO-1诱导PCa细胞抑制AR激活通过降低前列腺特异性抗原（PSA）启动子活性和mRNA水平。引人注目的是，这是第一份报告显示，通过染色质免疫沉淀分析，HO-1协会的基因启动子，揭示了一个新的功能HO-1在细胞核中。此外，HO-1和STAT 3直接相互作用，如通过免疫共沉淀研究所确定的。HO-1的强制表达增加了STAT 3的细胞质滞留。当用组成型活性STAT 3突变体转染PCa细胞时，PSA和STAT 3下游靶基因在氯化血红素处理下被废除。此外，在这些细胞的核部分中检测到pSTAT 3蛋白水平的显著降低。共聚焦显微镜图像显示在氯化血红素处理下AR/STAT 3核共定位率降低。体内研究证实，STAT 3核定界显着减少在PC 3肿瘤过度表达HO-1生长的裸鼠异种移植瘤。这些结果为HO-1下调PCa中AR转录活性提供了一种新功能，干扰STAT 3信号传导，证明其作用超出了血红素降解范围。Neoplasia（2012）14，1043-1056
Activation of the androgen receptor (AR) is a key step in the development of prostate cancer (PCa). Several mechanisms have been identified in AR activation, among them signal transducer and activator of transcription 3 (STAT3) signaling. Disruption of STAT3 activity has been associated to cancer progression. Recent studies suggest that heme oxygenase 1 (HO-1) may play a key role in PCa that may be independent of its catalytic function. We sought to explore whether HO-1 operates on AR transcriptional activity through the STAT3 axis. Our results display that HO-1 induction in PCa cells represses AR activation by decreasing the prostate-specific antigen (PSA) promoter activity and mRNA levels. Strikingly, this is the first report to show by chromatin immunoprecipitation analysis that HO-1 associates to gene promoters, revealing a novel function for HO-1 in the nucleus. Furthermore, HO-1 and STAT3 directly interact as determined by co-immunoprecipitation studies. Forced expression of HO-1 increases STAT3 cytoplasmic retention. When PCa cells were transfected with a constitutively active STAT3 mutant, PSA and STAT3 downstream target genes were abrogated under hemin treatment. Additionally, a significant decrease in pSTAT3 protein levels was detected in the nuclear fraction of these cells. Confocal microscopy images exhibit a decreased rate of AR/STAT3 nuclear co-localization under hemin treatment. In vivo studies confirmed that STAT3 nuclear delimitation was significantly decreased in PC3 tumors overexpressing HO-1 grown as xenografts in nude mice. These results provide a novel function for HO-1 down-modulating AR transcriptional activity in PCa, interfering with STAT3 signaling, evidencing its role beyond heme degradation. Neoplasia (2012) 14, 1043-1056