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首页> 外文期刊>Cellular Signalling >Promoter methylation induced epigenetic silencing of DAZAP2, a downstream effector of p38/MAPK pathway, in multiple myeloma cells
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Promoter methylation induced epigenetic silencing of DAZAP2, a downstream effector of p38/MAPK pathway, in multiple myeloma cells

机译：促进剂甲基化诱导Dazap2的表观遗传沉默，多发性骨髓瘤细胞中P38 / MAPK途径的下游效应器

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摘要

Multiple myeloma (MM) is hematological malignancy characterized by clonal proliferation of malignant plasma cells in the bone marrow environment. Previously, we identified DAZAP2 as a candidate cancer suppressor gene, the downregulation of which is regulated by its own promoter methylation status. In the current study, we analyzed the DAZAP2 promoter in MM cell lines KM3, MM.1S, OPM-2, and ARH77 by bisulfite genomic sequencing assay. We identified the binding site for transcription factor cyclic adenosine monophosphate response element binding (CREB) in the DAZAP2 promoter CpG2, and we found that hypermethylation of the CREB binding motif in the DAZAP2 promoter is responsible for the reduced DAZAP2 expression in MM cells. Later we checked the p38/MAPK signaling cascade, which is reported to regulate expression and function of CREB. Our results showed that the p38/MAPK signaling pathway drives the expression of DAZAP2 by phosphorylation of CREB, and hypermethylation of CREB binding motif in DAZAP2 promoter can inhibit binding of CREB to the latter, thus downregulating DAZAP2 expression. Moreover, treating the MM cells with 5-aza-2' deoxycytidine to demethylate DAZAP2 promoter restored the binding of CREB to its binding motif, and thus upregulated DAZAP2 expression. Our results not only identified DAZAP2 as a new downstream target of p38/MAPK/CREB signaling cascade, but we also clarified that the downregulation of DAZAP2 in MM cells is caused by hypermethylation of CREB binding motif in its own promoter region, which implies that demethylation of DAZAP2 promoter can be a novel therapeutic strategy for MM treatment.
机译：多发性骨髓瘤（mm）是骨髓环境中恶性血浆细胞克隆增殖的血液恶性肿瘤。以前，我们将Dazap2鉴定为候选癌症抑制基因，其下调由其自身启动子甲基化状态调节。在目前的研究中，我们通过双硫酸氢盐基因组测序测定分析了MM细胞系中的Dazap2启动子。我们鉴定了Dazap2启动子CpG2中的转录因子环状腺苷一磷酸二磷酸响应元结合（CREB）的结合位点，并且发现Dazap2启动子中CREB结合基序的高甲基化是在MM细胞中减少的DazaP2表达的原因。后来我们检查了P38 / MAPK信令级联，据报道，调节CREB的表达和功能。我们的结果表明，P38 / MAPK信号通路通过CREB的磷酸化驱动Dazap2的表达，Dazap2启动子中CREB结合基序的高甲基化可以抑制CREB对后者的结合，从而下调Dazap2表达。此外，将具有5-AZA-2'DoOxycididine的MM细胞与去甲基化物DazaP2启动子恢复到其结合基序的结合，因此上调的Dazap2表达。我们的结果不仅将Dazap2识别为P38 / MAPK / CREB信号级联的新下游靶标，但我们还阐明了Dazap2在MM细胞的下调是由其自身启动子区中的Creb结合基序的高甲基化引起的，这意味着去甲基化Dazap2启动子可以是MM治疗的新型治疗策略。

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  • 来源
    《Cellular Signalling》 |2019年第2019期|共10页
  • 作者

    Li Jiang; Hu Wei-Xin; Luo Sai-Qun; Xiong De-Hui; Sun Shuming; Wang Yan-Peng; Bu Xiu-Fen; Liu Jing; Hu Jingping;

  • 作者单位

    Cent S Univ Mol Biol Res Ctr Sch Life Sci 110 Xiangya Rd Changsha 410078 Hunan Peoples R China;

    Cent S Univ Mol Biol Res Ctr Sch Life Sci 110 Xiangya Rd Changsha 410078 Hunan Peoples R China;

    Cent S Univ Mol Biol Res Ctr Sch Life Sci 110 Xiangya Rd Changsha 410078 Hunan Peoples R China;

    Cent S Univ Mol Biol Res Ctr Sch Life Sci 110 Xiangya Rd Changsha 410078 Hunan Peoples R China;

    Cent S Univ Mol Biol Res Ctr Sch Life Sci 110 Xiangya Rd Changsha 410078 Hunan Peoples R China;

    Cent S Univ Mol Biol Res Ctr Sch Life Sci 110 Xiangya Rd Changsha 410078 Hunan Peoples R China;

    Cent S Univ Mol Biol Res Ctr Sch Life Sci 110 Xiangya Rd Changsha 410078 Hunan Peoples R China;

    Cent S Univ Mol Biol Res Ctr Sch Life Sci 110 Xiangya Rd Changsha 410078 Hunan Peoples R China;

    Cent S Univ Mol Biol Res Ctr Sch Life Sci 110 Xiangya Rd Changsha 410078 Hunan Peoples R China;

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  • 正文语种 eng
  • 中图分类 细胞形态学;
  • 关键词

    Multiple myeloma; DAZAP2; CREB; p38/MAPK;

    机译：多发性骨髓瘤;Dazap2;CREB;P38 / MAPK;

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