Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
Department of General Surgery, Shanghai Children's Medical Center, Shanghai, China.
Biochem Biophys Res Commun. 2014 Jun 20;449(1):1-7. doi: 10.1016/j.bbrc.2014.04.126. Epub 2014 May 4.
A number of JmjC domain-containing histone demethylases have been identified and biochemically characterized in mammalian. JMJD2A is a transcriptional cofactor and enzyme that catalyzes demethylation of histone H3 lysines 9 and 36. Here in this study, we aim to explore the role of JMJD2A in human gastric cancer. Quantitative real-time PCR, Western blot and immunohistochemistry analyses reveal higher expression of JMJD2A in clinical gastric cancer tissues than that in normal gastric mucosa. JMJD2A expression is associated with tumor stage and nodal status, and high level of JMJD2A predicts poor overall and disease-free survival. Univariate and multivariate survival analyses demonstrate that JMJD2A could serve as an independent prognostic factor. Furthermore, we show that inhibition the expression of JMJD2A attenuates the growth and transformation of three lines of gastric cancer cells. Mechanically, JMJD2A knockdown induces apoptosis of gastric cancer cells by up-regulating the expression of pro-apoptotic proteins and by down-regulating anti-apoptotic protein. Finally, we show that JMJD2A level is correlated with the level of the pro-apoptotic microRNA miR-34a in gastric cancer tissues and JMJD2A represses the expression of miR-34a by decreasing its promoter activity. Those findings demonstrate that JMJD2A regulates gastric cancer growth and serves as an independent prognostic factor, and implicate that JMJD2A may be a promising target for intervention.
许多含有 JmjC 结构域的组蛋白去甲基酶已经在哺乳动物中被鉴定和生化特征分析。JMJD2A 是一种转录共因子和酶，它催化组蛋白 H3 赖氨酸 9 和 36 的去甲基化。在本研究中，我们旨在探索 JMJD2A 在人类胃癌中的作用。定量实时 PCR、Western blot 和免疫组织化学分析显示，临床胃癌组织中 JMJD2A 的表达高于正常胃黏膜。JMJD2A 的表达与肿瘤分期和淋巴结状态有关，高水平的 JMJD2A 预示着整体和无病生存率较差。单因素和多因素生存分析表明，JMJD2A 可以作为一个独立的预后因素。此外，我们表明抑制 JMJD2A 的表达可减弱三条胃癌细胞系的生长和转化。机制上，JMJD2A 下调通过上调促凋亡蛋白和下调抗凋亡蛋白的表达诱导胃癌细胞凋亡。最后，我们表明 JMJD2A 水平与胃癌组织中促凋亡 microRNA miR-34a 的水平相关，JMJD2A 通过降低其启动子活性抑制 miR-34a 的表达。这些发现表明 JMJD2A 调节胃癌的生长并作为一个独立的预后因素，暗示 JMJD2A 可能是一个有前途的干预靶点。
