Authors' Affiliations: Cancer Science Institute of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Department of Biological Sciences, Nanyang Technological University; Institute of Molecular and Cell Biology (A*STAR); and Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.
Authors' Affiliations: Cancer Science Institute of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Department of Biological Sciences, Nanyang Technological University; Institute of Molecular and Cell Biology (A*STAR); and Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, SingaporeAuthors' Affiliations: Cancer Science Institute of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Department of Biological Sciences, Nanyang Technological University; Institute of Molecular and Cell Biology (A*STAR); and Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, SingaporeAuthors' Affiliations: Cancer Science Institute of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Department of Biological Sciences, Nanyang Technological University; Institute of Molecular and Cell Biology (A*STAR); and Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore
Cancer Res. 2014 Jun 1;74(11):3043-53. doi: 10.1158/0008-5472.CAN-13-2321. Epub 2014 Mar 31.
PRL-3, an oncogenic dual-specificity phosphatase, is overexpressed in 50% of acute myelogenous leukemia (AML) and associated with poor survival. We found that stable expression of PRL-3 confers cytokine independence and growth advantage of AML cells. However, how PRL-3 mediates these functions in AML is not known. To comprehensively screen for PRL3-regulated proteins in AML, we performed SILAC-based quantitative proteomics analysis and discovered 398 significantly perturbed proteins after PRL-3 overexpression. We show that Leo1, a component of RNA polymerase II-associated factor (PAF) complex, is a novel and important mediator of PRL-3 oncogenic activities in AML. We described a novel mechanism where elevated PRL-3 protein increases JMJD2C histone demethylase occupancy on Leo1 promoter, thereby reducing the H3K9me3 repressive signals and promoting Leo1 gene expression. Furthermore, PRL-3 and Leo1 levels were positively associated in AML patient samples (N=24; P<0.01). On the other hand, inhibition of Leo1 reverses PRL-3 oncogenic phenotypes in AML. Loss of Leo1 leads to destabilization of the PAF complex and downregulation of SOX2 and SOX4, potent oncogenes in myeloid transformation. In conclusion, we identify an important and novel mechanism by which PRL-3 mediates its oncogenic function in AML.
PRL-3 是一种致癌的双特异性磷酸酶，在 50%的急性髓系白血病（AML）中过度表达，并与不良预后相关。我们发现 PRL-3 的稳定表达赋予了 AML 细胞对细胞因子的独立性和生长优势。然而，PRL-3 如何在 AML 中介导这些功能尚不清楚。为了全面筛选 AML 中 PRL3 调节的蛋白，我们进行了基于 SILAC 的定量蛋白质组学分析，发现 PRL-3 过表达后有 398 个显著失调的蛋白。我们表明，Leo1 是 RNA 聚合酶 II 相关因子（PAF）复合物的一个组成部分，是 PRL-3 在 AML 中致癌活性的一个新的重要介质。我们描述了一个新的机制，即升高的 PRL-3 蛋白增加 JMJD2C 组蛋白去甲基酶在 Leo1 启动子上的占据，从而减少 H3K9me3 抑制信号，促进 Leo1 基因表达。此外，在 AML 患者样本（N=24；P<0.01）中，PRL-3 和 Leo1 的水平呈正相关。另一方面，抑制 Leo1 可逆转 PRL-3 在 AML 中的致癌表型。Leo1 的缺失导致 PAF 复合物的不稳定性和 SOX2 和 SOX4 的下调，SOX2 和 SOX4 是髓系转化中的强效癌基因。总之，我们确定了 PRL-3 在 AML 中发挥其致癌功能的一个重要而新颖的机制。
