MAX 失活导致小细胞肺癌中 MYC-SWI/SNF 程序紊乱，并与 BRG1 产生合成致死性。
MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1.
机构信息
1Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC); 2Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona; 3Instituto de Biomedicina de Sevilla (IBiS), 4Department of Pathology, Hospital Universitario Virgen del Rocío, Consejo Superior de Investigaciones Cientificas (CSIC), Universidad de Sevilla, Seville; 5Division of Oncology, Centro para la Investigación Medica Aplicada (CIMA), University of Navarre, Pamplona, Spain; 6MRC-Holland, Amsterdam, the Netherlands; and 7Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
出版信息
Cancer Discov. 2014 Mar;4(3):292-303. doi: 10.1158/2159-8290.CD-13-0799. Epub 2013 Dec 20.
Our knowledge of small cell lung cancer (SCLC) genetics is still very limited, amplification of L-MYC, N-MYC, and C-MYC being some of the well-established gene alterations. Here, we report our discovery of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in SCLC. MAX inactivation is mutually exclusive with alterations of MYC and BRG1, the latter coding for an ATPase of the switch/sucrose nonfermentable (SWI/SNF) complex. We demonstrate that BRG1 regulates the expression of MAX through direct recruitment to the MAX promoter, and that depletion of BRG1 strongly hinders cell growth, specifically in MAX-deficient cells, heralding a synthetic lethal interaction. Furthermore, MAX requires BRG1 to activate neuroendocrine transcriptional programs and to upregulate MYC targets, such as glycolysis-related genes. Finally, inactivation of the MAX dimerization protein, MGA, was also observed in both non-small cell lung cancer and SCLC. Our results provide evidence that an aberrant SWI/SNF-MYC network is essential for lung cancer development.
我们对小细胞肺癌（SCLC）遗传学的了解仍然非常有限，其中包括 L-MYC、N-MYC 和 C-MYC 的扩增等一些已确立的基因改变。在这里，我们报告了我们在 SCLC 中发现的 MYC 相关因子 X 基因 MAX 的肿瘤特异性失活。MAX 失活与 MYC 和 BRG1 的改变是相互排斥的，后者编码 SWI/SNF 复合物的 ATP 酶。我们证明 BRG1 通过直接募集到 MAX 启动子来调节 MAX 的表达，并且 BRG1 的耗竭强烈阻碍细胞生长，特别是在 MAX 缺陷细胞中，预示着合成致死相互作用。此外，MAX 需要 BRG1 来激活神经内分泌转录程序，并上调 MYC 靶标，如糖酵解相关基因。最后，还观察到非小细胞肺癌和 SCLC 中 MAX 二聚化蛋白 MGA 的失活。我们的结果提供了证据，表明异常的 SWI/SNF-MYC 网络对于肺癌的发展是必不可少的。
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