The Histone Demethylase JMJD2B Plays an Essential Role in Human Carcinogenesis through Positive Regulation of Cyclin-Dependent Kinase 6
The Histone Demethylase JMJD2B Plays an Essential Role in Human Carcinogenesis through Positive Regulation of Cyclin-Dependent Kinase 6
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DOI：
10.1158/1940-6207.capr-11-0290
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发表时间：
2011-12-01
影响因子：
3.3
通讯作者：
Hamamoto, Ryuji
中科院分区：
文献类型：
--
作者：
Toyokawa, Gouji;Cho, Hyun-Soo;Hamamoto, Ryuji
已知组蛋白甲基转移酶和去甲基化酶通过改变组蛋白上的表观遗传标记来调节转录，但它们的功能障碍在人类疾病（如癌症）中的病理作用仍有待阐明。在此，我们表明，组蛋白去甲基化酶JMJD 2B参与人类致癌。实时荧光定量PCR显示膀胱癌组织中JMJD 2B的表达水平显著高于相应的非肿瘤组织（P < 0.0001），免疫组化证实了JMJD 2B蛋白表达的升高。此外，cDNA微阵列分析显示肺癌中JMJD 2B的反式激活，免疫组化分析显示肺癌中的蛋白过表达。siRNA介导的膀胱癌和肺癌细胞系中JMJD 2B表达的降低显著抑制癌细胞的增殖，并且抑制JMJD 2B表达导致S期癌细胞群体减少，同时G（1）期细胞增加。此外，克隆形成试验表明，JM JD 2B的脱甲基酶活性具有致癌活性。敲低JMJD 2B后的微阵列分析显示，JMJD 2B可以调节包括细胞周期通路在内的多种有助于致癌的通路。在下游基因中，染色质免疫沉淀显示，CDK 6（细胞周期蛋白依赖性激酶6），在G（1）-S转换中必不可少，直接受JMJD 2B的调控，通过组蛋白H3-K9在其启动子区的去甲基化。JMJD 2B和CDK 6的表达水平在各种类型的细胞系中显著相关。组蛋白去甲基化的失调导致细胞周期的扰动，代表了人类癌症发生的新机制，JMJD 2B是抗癌治疗的可行分子靶点。Cancer Prev Res; 4（12）; 2051-61. (C)2011年AACR。
Histone methyltransferases and demethylases are known to regulate transcription by altering the epigenetic marks on histones, but the pathologic roles of their dysfunction in human diseases, such as cancer, still remain to be elucidated. Herein, we show that the histone demethylase JMJD2B is involved in human carcinogenesis. Quantitative real-time PCR showed notably elevated levels of JMJD2B expression in bladder cancers, compared with corresponding nonneoplastic tissues (P < 0.0001), and elevated protein expression was confirmed by immunohistochemistry. In addition, cDNA microarray analysis revealed transactivation of JMJD2B in lung cancer, and immunohistochemical analysis showed protein overexpression in lung cancer. siRNA-mediated reduction of expression of JMJD2B in bladder and lung cancer cell lines significantly suppressed the proliferation of cancer cells, and suppressing JMJD2B expression lead to a decreased population of cancer cells in S phase, with a concomitant increase of cells in G(1) phase. Furthermore, a clonogenicity assay showed that the demethylase activity of JMJD2B possesses an oncogenic activity. Microarray analysis after knockdown of JMJD2B revealed that JMJD2B could regulate multiple pathways which contribute to carcinogenesis, including the cell-cycle pathway. Of the downstream genes, chromatin immunoprecipitation showed that CDK6 (cyclin-dependent kinase 6), essential in G(1)-S transition, was directly regulated by JMJD2B, via demethylation of histone H3-K9 in its promoter region. Expression levels of JMJD2B and CDK6 were significantly correlated in various types of cell lines. Deregulation of histone demethylation resulting in perturbation of the cell cycle, represents a novel mechanism for human carcinogenesis and JMJD2B is a feasible molecular target for anticancer therapy. Cancer Prev Res; 4(12); 2051-61. (C) 2011 AACR.