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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eμ-miR-155 transgenic mouse model
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miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eμ-miR-155 transgenic mouse model

机译：miR-155在Eμ-miR-155转基因小鼠模型中靶向组蛋白脱乙酰基酶4（HDAC4），并损害B细胞淋巴瘤6（BCL6）的转录活性

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摘要

Multiple studies have established that microRNAs (miRNAs) are involved in the initiation and progression of cancer. Notably, miR-155 is one of the most overexpressed miRNAs in several solid and hematological malignancies. Ectopic miR-155 expression in mice B cells (Eμ-miR-155 transgenic mice) has been shown to induce pre-B-cell proliferation followed by high-grade lymphoma/leukemia. Loss of miR-155 in mice resulted in impaired immunity due to defective T-cell-mediated immune response. Here we provide a mechanistic insight into miR-155-induced leukemogenesis in the Eμ-miR-155 mouse model through genome-wide transcriptome analysis of naïve B cells and target studies. We found that a key transcriptional repressor and proto-oncogene, Bd6 is significantly down-regulated in Eu-miR-155 mice. The reduction of Bcl6 subsequently leads to de-repression of some of the known Bcl6 targets like inhibitor of differentiation (ld2), interleukin-6 (IL6), cMyc, Cyclin D1, and Mip1α/ccl3, all of which promote cell survival and proliferation. We show that Bd6 is indirectly regulated by miR-155 through Mxd1/Mad1 up-regulation. Interestingly, we found that miR-155 directly targets HDAC4, a corepressor partner of BCL6. Furthermore, ectopic expression of HDAC4 in human-activated B-cell-type diffuse large B-cell lymphoma (DLBCL) cells results in reduced miR-155-induced proliferation, clonogenic potential, and increased apoptosis. Meta-analysis of the diffuse large B-cell lymphoma patient microarray data showed that miR-155 expression is inversely correlated with Bcl6 and Hdac4. Hence this study provides a better understanding of how miR-155 causes disruption of the BCL6 transcriptional machinery that leads to up-regulation of the survival and proliferation genes in miR-155-induced leukemias.
机译：多项研究已经确定，microRNA（miRNA）与癌症的发生和发展有关。值得注意的是，miR-155是几种实体和血液系统恶性肿瘤中表达最严重的miRNA之一。已显示小鼠B细胞（Eμ-miR-155转基因小鼠）中异位miR-155的表达可诱导B细胞前增殖，继而引起高度淋巴瘤/白血病。由于缺陷的T细胞介导的免疫反应，miR-155在小鼠体内的丧失导致免疫功能受损。在这里，我们通过对幼稚B细胞的全基因组转录组分析和靶标研究，提供了对Eμ-miR-155小鼠模型中miR-155诱导的白血病发生的机制性见解。我们发现，关键的转录阻遏物和原癌基因Bd6在Eu-miR-155小鼠中显着下调。 Bcl6的减少随后导致一些已知Bcl6靶标的抑制，如分化抑制剂（ld2），白介素6（IL6），cMyc，Cyclin D1和Mip1α/ ccl3，所有这些都能促进细胞存活和增殖。 。我们表明，Bd6通过Mxd1 / Mad1上调被miR-155间接调节。有趣的是，我们发现miR-155直接靶向BCL6的核心表达伴侣HDAC4。此外，HDAC4在人激活的B细胞型弥漫性大B细胞淋巴瘤（DLBCL）细胞中的异位表达导致miR-155诱导的增殖减少，克隆形成潜力和凋亡增加。对弥漫性大B细胞淋巴瘤患者微阵列数据的荟萃分析显示，miR-155表达与Bcl6和Hdac4呈负相关。因此，本研究更好地了解了miR-155如何引起BCL6转录机制的破坏，从而导致miR-155诱导的白血病中存活和增殖基因的上调。

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  • 作者

    Sukhinder K. Sandhu; Stefano Volinia; Stefan Costinean; Marco Galasso; Reid Neinast; Ramasamy Santhanam; Mark R. Parthun; Danilo Perrotti; Guido Marcucci; Ramiro Garzon; Carlo M. Croce;

  • 作者单位

    Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Medical Center, Columbus, OH 43210;

    Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Medical Center, Columbus, OH 43210,Data Mining for Analysis of Microarrays, Department of Morphology and Embryology, Universita degli Studi, Ferrara 44100, Italy;

    Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Medical Center, Columbus, OH 43210;

    Data Mining for Analysis of Microarrays, Department of Morphology and Embryology, Universita degli Studi, Ferrara 44100, Italy;

    Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Medical Center, Columbus, OH 43210;

    Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Medical Center, Columbus, OH 43210;

    Department of Molecular and Cellular Biochemistry and Ohio State University Medical Center, Columbus, OH 43210;

    Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Medical Center, Columbus, OH 43210;

    Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Medical Center, Columbus, OH 43210,Division of Hematology, Department of Internal Medicine, Ohio State University Medical Center, Columbus, OH 43210;

    Division of Hematology, Department of Internal Medicine, Ohio State University Medical Center, Columbus, OH 43210;

    Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Medical Center, Columbus, OH 43210;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    NfκB; ingenuity pathway analysis;

    机译：NfκB;创造力途径分析;

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