MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1.
Cancer Discov
; 4(3): 292-303, 2014 Mar.
Article
en En
| MEDLINE
| ID: mdl-24362264
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.
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1
Bases de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
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Proteínas Nucleares
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Carcinoma de Pulmón de Células no Pequeñas
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ADN Helicasas
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice
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Carcinoma Pulmonar de Células Pequeñas
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Neoplasias Pulmonares
Límite:
Humans
Idioma:
En
Revista:
Cancer Discov
Año:
2014
Tipo del documento:
Article