Negative regulation of miR-1275 by H3K27me3 is critical for glial induction of glioblastoma cells
Negative regulation of miR-1275 by H3K27me3 is critical for glial induction of glioblastoma cells
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H3K27me3 对 miR-1275 的负调控对于胶质母细胞瘤细胞的神经胶质诱导至关重要
DOI：
10.1002/1878-0261.12525
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发表时间：
2019-07-01
影响因子：
6.6
通讯作者：
Zhu, Wenbo
中科院分区：
文献类型：
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作者：
Mai, Jialuo;Gu, Jiayu;Zhu, Wenbo
环磷酸腺苷/蛋白激酶A(cAMP/PKA)通路的激活可诱导胶质母细胞瘤(GBM)细胞分化，但microRNA(MiRNA)调控这一过程的机制尚不清楚。在这项研究中，通过对二丁酰cAMP处理的GBM细胞进行miRNA基因组学和功能丧失和功能获得的分析，我们确定了一个关键的负调控因子hsa-miR-1275，它调控一系列参与癌症进展、干细胞维持以及细胞成熟和分化的基因。此外，我们证实miR-1275直接和负向调节胶质纤维酸性蛋白(GFAP)的蛋白表达，GFAP是成熟星形胶质细胞的标志。值得注意的是，三甲基组蛋白H3(Lys27)(H3K27me3)位于PKA/多梳抑制复合体2(PRC2)途径下游，是miR-1275下调的原因。此外，经二丁酰cAMP处理的原代培养的GBM细胞miR-1275表达降低，GFAP表达增加。在患者来源的胶质瘤干细胞肿瘤模型中，cAMP升降器和H3K27me3甲基转移酶抑制剂抑制肿瘤生长，诱导分化，并减少miR-1275的表达。综上所述，我们的研究表明，cAMP/PKA/PRC2/H3K27me3途径对miR-1275的表观遗传抑制介导了GBM细胞的胶质诱导，为诱导分化治疗提供了新的机制和新的靶点。
Activation of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway induces glial differentiation of glioblastoma (GBM) cells, but the mechanism by which microRNA (miRNA) regulate this process remains poorly understood. In this study, by performing miRNA genomics and loss- and gain-of-function assays in dibutyryl-cAMP-treated GBM cells, we identified a critical negative regulator, hsa-miR-1275, that modulates a set of genes involved in cancer progression, stem cell maintenance, and cell maturation and differentiation. Additionally, we confirmed that miR-1275 directly and negatively regulates the protein expression of glial fibrillary acidic protein (GFAP), a marker of mature astrocytes. Of note, tri-methyl-histone H3 (Lys27) (H3K27me3), downstream of the PKA/polycomb repressive complex 2 (PRC2) pathway, accounts for the downregulation of miR-1275. Furthermore, decreased miR-1275 expression and induction of GFAP expression were also observed in dibutyryl-cAMP-treated primary cultured GBM cells. In a patient-derived glioma stem cell tumor model, a cAMP elevator and an inhibitor of H3K27me3 methyltransferase inhibited tumor growth, induced differentiation, and reduced expression of miR-1275. In summary, our study shows that epigenetic inhibition of miR-1275 by the cAMP/PKA/PRC2/H3K27me3 pathway mediates glial induction of GBM cells, providing a new mechanism and novel targets for differentiation-inducing therapy.