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首页 » BIOON报道 » J Clin Invest.:组蛋白去甲基化酶或可作为非小细胞肺癌治疗靶点

J Clin Invest.:组蛋白去甲基化酶或可作为非小细胞肺癌治疗靶点

来源:生物谷 2013-11-11 01:01

2013年11月11日讯 /生物谷BIOON/--非小细胞肺癌(Non-small cell lung cancer ,NSCLC)是癌症中致死率非常高的一类肿瘤。现今采用的治疗方法是针对细胞内蛋白激酶,该方法对部分病人有效,但是还有部分病人对该治疗方法没有任何反应。

近期发表在Journal of Clinical Investigation上的文章表明整体性的DNA甲基化模式变化或导致非小细胞肺癌的形成。

美国安德森肿瘤研究中心的MinGyu Lee博士领导他的研究团队发现NSCLS细胞系中组蛋白甲基化发生变化,NSCLS细胞系组蛋白去甲基化酶KDM2A的表达量上调。

进一步研究实验发现KDM2A表达量上调会通过ERK1/2信号通路,增加细胞的扩增能力和侵染行。NSCLS病人评估也表明KDM2A上调与预后差有一定的相关性。

该研究表明针对KDM2A的治疗方法或对部分NSCLS病人有效。(生物谷Bioon.com)

KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling

Klaus W. Wagner, Hunain Alam, Shilpa S. Dhar, Uma Giri, Na Li, Yongkun Wei, Dipak Giri, Tina Cascone, Jae-Hwan Kim, Yuanqing Ye, Asha S. Multani, Chia-Hsin Chan, Baruch Erez, Babita Saigal, Jimyung Chung, Hui-Kuan Lin, Xifeng Wu, Mien-Chie Hung, John V. Heymach and Min Gyu Lee

Epigenetic dysregulation has emerged as a major contributor to tumorigenesis. Histone methylation is a well-established mechanism of epigenetic regulation that is dynamically modulated by histone methyltransferases and demethylases. The pathogenic role of histone methylation modifiers in non–small cell lung cancer (NSCLC), which is the leading cause of cancer deaths worldwide, remains largely unknown. Here, we found that the histone H3 lysine 36 (H3K36) demethylase KDM2A (also called FBXL11 and JHDM1A) is frequently overexpressed in NSCLC tumors and cell lines. KDM2A and its catalytic activity were required for in vitro proliferation and invasion of KDM2A-overexpressing NSCLC cells. KDM2A overexpression in NSCLC cells with low KDM2A levels increased cell proliferation and invasiveness. KDM2A knockdown abrogated tumor growth and invasive abilities of NSCLC cells in mouse xenograft models. We identified dual-specificity phosphatase 3 (DUSP3) as a key KDM2A target gene and found that DUSP3 dephosphorylates ERK1/2 in NSCLC cells. KDM2A activated ERK1/2 through epigenetic repression of DUSP3 expression via demethylation of dimethylated H3K36 at the DUSP3 locus. High KDM2A levels correlated with poor prognosis in NSCLC patients. These findings uncover an unexpected role for a histone methylation modifier in activating ERK1/2 in lung tumorigenesis and metastasis, suggesting that KDM2A may be a promising therapeutic target in NSCLC.

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