期刊
CANCER DISCOVERY
卷 4, 期 3, 页码 292-303出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-13-0799
关键词
-
类别
资金
- Spanish Ministry of Economy and Competitiveness [SAF2011-22897]
- Red Tematica de Investigacion del Cancer-RTICCs [RD12/0036/0045, RD12/0036/0040]
- Red de Biobancos [RD09/0076/00085]
- European Community [HEALTH-F2-2010-258677-CURELUNG]
- Ministry of Health, Labor and Welfare for the Third-term Comprehensive 10-year Strategy for Cancer Control, Japan
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. SIGNIFICANCE: We discovered that the MYC-associated factor X gene, MAX, is inactivated in SCLCs. Furthermore, we revealed a preferential toxicity of the inactivation of the chromatin remodeler BRG1 in MAX-deficient lung cancer cells, which opens novel therapeutic possibilities for the treatment of patients with SCLC with MAX-deficient tumors. (C) 2013 AACR.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据