Detalle Publicación

MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1

Autores: Romero, O. A.; Torres-Diz, M.; Pros, E. ; Savola, S. ; Gómez, A. ; Morán, S. ; Saez, C. ; Iwakawa, R.; Villanueva, A.; Montuenga Badía, Luis; Kohno, T.; Yokota, J.; Sanchez-Cespedes, M.
Título de la revista: CANCER DISCOVERY
ISSN: 2159-8274
Volumen: 4
Número: 3
Páginas: 292 - 303
Fecha de publicación: 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.