MAX Inactivation in Small Cell Lung Cancer Disrupts MYC–SWI/SNF Programs and Is Synthetic Lethal with BRG1
2014
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. Cancer Discov; 4(3); 292–303. ©2013 AACR .
See related commentary by Rudin and Poirier, [p. 273][1]
This article is highlighted in the In This Issue feature, [p. 259][2]
[1]: /lookup/volpage/4/273?iss=3
[2]: /lookup/volpage/4/259?iss=3
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