EZH2 promotes E2F-driven SCLC tumorigenesis through modulation of apoptosis and cell-cycle regulation.
EZH2 promotes E2F-driven SCLC tumorigenesis through modulation of apoptosis and cell-cycle regulation.
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DOI：
10.1097/jto.0b013e318298762f
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发表时间：
2013-08
期刊：
影响因子：
--
通讯作者：
Lam WL
中科院分区：
文献类型：
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作者：
Hubaux R;Thu KL;Coe BP;MacAulay C;Lam S;Lam WL
虽然EZH 2与非小细胞肺癌和小细胞肺癌都相关，但目前的观察表明EZH 2在这些肺癌类型中的激活和过表达的机制不同。在全球范围内，小细胞肺癌（SCLC）每年导致20万人死亡。需要新的临床方法用于SCLC治疗以改善较差的存活率。鉴于EZH 2作为靶点的治疗潜力，我们试图描述EZH 2破坏的下游后果，以鉴定EZH 2促进SCLC中肿瘤发生的细胞机制。我们产生了稳定表达靶向EZH 2的shRNA和相应对照（pLKO. 1）的细胞，并通过碘化丙啶染色和荧光激活细胞分选、western blot、qRT-PCR以及使用MTT测定的细胞活力评估来确定EZH 2敲低对细胞周期和凋亡的影响。我们发现EZH 2抑制1）通过上调促凋亡因子Puma和Bad增加凋亡活性，2）减少S或G2/M期的细胞分数，和3）升高p21蛋白水平，暗示EZH 2在SCLC中的细胞死亡和细胞周期控制中。我们的研究结果为EZH 2在细胞周期和凋亡调控中的作用提供了证据，为解释EZH 2在SCLC中的致瘤性提供了生物学机制。我们的工作指出了EZH 2作为小细胞肺癌治疗靶点的巨大潜力。
While EZH2 has been associated with both non small cell and small cell lung cancers, current observations suggest different mechanisms of EZH2 activation and overexpression in these lung cancer types. Globally, small cell lung cancer (SCLC) kills 200,000 people yearly. New clinical approaches for SCLC treatment are required to improve the poor survival rate. Given the therapeutic potential of EZH2 as a target, we sought to delineate the downstream consequences of EZH2 disruption to identify the cellular mechanisms by which EZH2 promotes tumorigenesis in SCLC. We generated cells with stable expression of shRNA targeting EZH2 and corresponding controls (pLKO.1) and determined the consequences of EZH2 knockdown on the cell cycle and apoptosis by means of propidium iodide staining and fluorescence activated cell sorting, western blot, qRT-PCR as well as cell viability assessment using MTT assays. We discovered that EZH2 inhibition 1) increased apoptotic activity by up-regulating the pro-apoptotic factors Puma and Bad, 2) decreased the fraction of cells in S or G2/M phases, and 3) elevated p21 protein levels, implicating EZH2 in cell death and cell cycle control in SCLC. Our findings present evidence for the role of EZH2 in the regulation of cell cycle and apoptosis, providing a biological mechanism to explain the tumorigenicity of EZH2 in SCLC. Our work points to the great potential of EZH2 as a therapeutic target in SCLC.