Activation of the aryl hydrocarbon receptor AhR Promotes retinoic acid-induced differentiation of myeloblastic leukemia cells by restricting expression of the stem cell transcription factor Oct4.
Activation of the aryl hydrocarbon receptor AhR Promotes retinoic acid-induced differentiation of myeloblastic leukemia cells by restricting expression of the stem cell transcription factor Oct4.
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DOI：
10.1158/0008-5472.can-10-2299
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发表时间：
2011-03-15
期刊：
影响因子：
11.2
通讯作者：
Yen A
中科院分区：
文献类型：
--
作者：
Bunaciu RP;Yen A
视黄酸（RA）通过其促进癌细胞分化的能力用于治疗白血病和其他癌症。增强RA抗癌作用的策略可以深化和扩大其有益的治疗应用。在这项研究中，我们描述了一个受体串扰系统，解决这个问题。RA的影响是由RAR/RXR受体介导的，我们表明，通过与芳烃受体（AhR），一种蛋白质作为转录因子和泛素连接酶复合物中的配体依赖性接头的相互作用进行修改。RAR/RXR和AhR途径在配体-受体以及受体-启动子相互作用的水平上相互干扰。在这里，我们评估了AhR在RA诱导的分化过程中的作用以及10月4日的假设收敛，AhR是一种被认为可以维持干细胞特征的转录因子。RA上调HL-60早幼粒白血病细胞分化过程中AhR表达，下调Oct 4表达。稳定转染子中AhR过表达下调了Oct 4，也降低了另一种干细胞相关因子ALDH 1活性，增强了RA诱导的分化，如与早期（CD 38和CD 11b）和晚期（嗜酸性呼吸爆发）反应相关的细胞分化标志物所示。AhR过表达也增加了激活的Raf 1的水平，这是已知的，以帮助推动RA诱导的分化。RNAi介导的Oct 4敲低增强了RA诱导的分化和G 0细胞周期阻滞。与Oct 4下调对分化的假设重要性一致，通过每两周一次的高RA暴露而对RA产生抗性的亲本细胞显示出升高的Oct 4水平，其未能被下调。总之，我们的研究结果表明，RA诱导的白血病分化的治疗效果取决于AhR及其下调干细胞因子Oct 4的能力。
Retinoic acid (RA) is used to treat leukemia and other cancers through its ability to promote cancer cell differentiation. Strategies to enhance the anti-cancer effects of RA could deepen and broaden its beneficial therapeutic applications. In this study, we describe a receptor crosstalk system that addresses this issue. RA effects are mediated by RAR/RXR receptors that we show are modified by interactions with the aryl hydrocarbon receptor (AhR), a protein functioning both as a transcription factor and a ligand-dependent adaptor in an ubiquitin ligase complex. RAR/RXR and AhR pathways crosstalk at the levels of ligand-receptor and also receptor - promoter interactions. Here we assessed the role of AhR during RA-induced differentiation and an hypothesized convergence at Oct4, a transcription factor believed to maintain stem cell characteristics. RA upregulated AhR and downregulated Oct4 during differentiation of HL-60 promyelocytic leukemia cells. AhR overexpression in stable transfectants downregulated Oct4 and also decreased ALDH1 activity, another stem cell associated factor, enhancing RA-induced differentiation as indicated by cell differentiation markers associated with early (CD38 and CD11b) and late (neutrophilic respiratory burst) responses. AhR overexpression also increased levels of activated Raf1, which is known to help propel RA-induced differentiation. RNAi-mediated knockdown of Oct4 enhanced RA-induced differentiation and G0 cell cycle arrest relative to parental cells. Consistent with the hypothesized importance of Oct4 downregulation for differentiation, parental cells rendered resistant to RA by biweekly high RA exposure displayed elevated Oct4 levels that failed to be downregulated. Together, our results suggested that therapeutic effects of RA-induced leukemia differentiation depend on AhR and its ability to downregulate the stem cell factor Oct4.