Sbirkov Yordan, Kwok Colin, Bhamra Amandeep, Thompson Andrew J, Gil Veronica, Zelent Arthur, Petrie Kevin
Theodor Boveri Institute and Comprehensive Cancer Center Mainfranken, Biocenter, University of Würzburg, Würzburg 97074, Germany.
Division of Clinical Studies, Institute of Cancer Research, London SW7 3RP, UK.
Int J Mol Sci. 2017 Jul 5;18(7):1440. doi: 10.3390/ijms18071440.
Alterations to the gene encoding the EZH2 (KMT6A) methyltransferase, including both gain-of-function and loss-of-function, have been linked to a variety of haematological malignancies and solid tumours, suggesting a complex, context-dependent role of this methyltransferase. The successful implementation of molecularly targeted therapies against EZH2 requires a greater understanding of the potential mechanisms by which EZH2 contributes to cancer. One aspect of this effort is the mapping of EZH2 partner proteins and cellular targets. To this end we performed affinity-purification mass spectrometry in the FAB-M2 HL-60 acute myeloid leukaemia (AML) cell line before and after all- retinoic acid-induced differentiation. These studies identified new EZH2 interaction partners and potential non-histone substrates for EZH2-mediated methylation. Our results suggest that EZH2 is involved in the regulation of translation through interactions with a number of RNA binding proteins and by methylating key components of protein synthesis such as eEF1A1. Given that deregulated mRNA translation is a frequent feature of cancer and that eEF1A1 is highly expressed in many human tumours, these findings present new possibilities for the therapeutic targeting of EZH2 in AML.
编码EZH2（KMT6A）甲基转移酶的基因改变，包括功能获得和功能丧失，都与多种血液系统恶性肿瘤和实体瘤有关，这表明该甲基转移酶具有复杂的、依赖于背景的作用。成功实施针对EZH2的分子靶向治疗需要更深入了解EZH2促成癌症的潜在机制。这项工作的一个方面是绘制EZH2伴侣蛋白和细胞靶点。为此，我们在全反式维甲酸诱导分化前后的FAB-M2 HL-60急性髓系白血病（AML）细胞系中进行了亲和纯化质谱分析。这些研究确定了新的EZH2相互作用伴侣以及EZH2介导甲基化的潜在非组蛋白底物。我们的结果表明，EZH2通过与多种RNA结合蛋白相互作用并甲基化蛋白质合成的关键成分（如eEF1A1）参与翻译调控。鉴于失调的mRNA翻译是癌症的常见特征，且eEF1A1在许多人类肿瘤中高度表达，这些发现为AML中EZH2的治疗靶向提供了新的可能性。
