A number of JmjC domain-containing histone demethylases have been identified and biochemically characterized in mammalian models and humans. JMJD2A is a transcriptional co-factor and enzyme that catalyzes the demethylation of histone H3 lysine 9 and 36 (H3K9 and H3K36). Here in this study, we reported the role of JMJD2A in human glioma. Quantitative real-time PCR and western blot were performed to analyzed JMJD2A expression in glioma. Log-rank was performed to plot the survival curve. JMJD2A was knocked or overexpressed with lentivirus. Cell proliferation and colony formation were performed to assess the effects of JMJD2A on glioma cell growth. Xenograft experiment was performed the evaluate the growth rate of glioma cells in vivo. The signaling pathway was analyzed with western blot and mTOR was inhibited with rapamycin. Quantitative real-time PCR and western blot experiments revealed higher expression of JMJD2A and lower levels of H3K9me3/H3K36me3 in glioma tissues than that in normal brain tissues. We showed that knockdown of JMJD2A expression attenuated the growth and colony formation in three lines of glioma cells (U251, T98G, and U87MG), whereas JMJD2A overexpression resulted in opposing effects. Furthermore, we performed in vivo xenograft experiments and our data demonstrated that JMJD2A knockdown reduced the growth of glioma T98G cells in vivo. Further mechanism study implicated that JMJD2A activated the Akt-mTOR pathway and promoted protein synthesis in glioma cells via promoting phosphoinositide-dependent kinase-1 (PDK1) expression. The activation of the Akt-mTOR pathway was also validated in human glioma tissues. Finally, we showed that inhibition of mTOR with rapamycin blocked the effects of JMJD2A on protein synthesis, cell proliferation and colony formation of glioma cells. These findings demonstrated that JMJD2A regulated glioma growth and implicated that JMJD2A might be a promising target for intervention.

中文翻译：

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组蛋白去甲基化酶 JMJD2A 通过靶向 Akt-mTOR 信号促进胶质瘤细胞生长

已在哺乳动物模型和人类中鉴定出许多含有 JmjC 结构域的组蛋白去甲基化酶并对其进行生化表征。JMJD2A 是一种转录辅因子和酶，可催化组蛋白 H3 赖氨酸 9 和 36（H3K9 和 H3K36）去甲基化。在这项研究中，我们报告了 JMJD2A 在人类神经胶质瘤中的作用。进行定量实时 PCR 和蛋白质印迹以分析神经胶质瘤中 JMJD2A 的表达。执行对数秩以绘制生存曲线。JMJD2A 被慢病毒敲除或过表达。进行细胞增殖和集落形成以评估 JMJD2A 对胶质瘤细胞生长的影响。进行异种移植实验以评估体内胶质瘤细胞的生长速率。用蛋白质印迹分析信号通路，用雷帕霉素抑制mTOR。定量实时 PCR 和蛋白质印迹实验显示神经胶质瘤组织中 JMJD2A 的表达高于正常脑组织中的 H3K9me3/H3K36me3 水平。我们发现 JMJD2A 表达的敲低减弱了三系胶质瘤细胞（U251、T98G 和 U87MG）的生长和集落形成，而 JMJD2A 过表达导致相反的效果。此外，我们进行了体内异种移植实验，我们的数据表明 JMJD2A 敲低减少了体内胶质瘤 T98G 细胞的生长。进一步的机制研究表明，JMJD2A 通过促进磷酸肌醇依赖性激酶-1 (PDK1) 的表达激活 Akt-mTOR 通路并促进胶质瘤细胞中的蛋白质合成。Akt-mTOR 通路的激活也在人类神经胶质瘤组织中得到验证。最后，我们发现用雷帕霉素抑制 mTOR 可阻断 JMJD2A 对蛋白质合成、细胞增殖和胶质瘤细胞集落形成的影响。这些发现表明 JMJD2A 调节胶质瘤的生长，并暗示 JMJD2A 可能是一个有希望的干预目标。