title: MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1.
abstract: 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.
authors.affiliation: 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.
authors.forename: Octavio A
authors.initials: OA
authors.lastname: Romero
authors.forename: Manuel
authors.initials: M
authors.lastname: Torres-Diz
authors.forename: Eva
authors.initials: E
authors.lastname: Pros
authors.forename: Suvi
authors.initials: S
authors.lastname: Savola
authors.forename: Antonio
authors.initials: A
authors.lastname: Gomez
authors.forename: Sebastian
authors.initials: S
authors.lastname: Moran
authors.forename: Carmen
authors.initials: C
authors.lastname: Saez
authors.forename: Reika
authors.initials: R
authors.lastname: Iwakawa
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.forename: Luis M
authors.initials: LM
authors.lastname: Montuenga
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
authors.forename: Montse
authors.initials: M
authors.lastname: Sanchez-Cespedes
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D004265:DNA Helicases; D009687:Nuclear Proteins; D014157:Transcription Factors; C499330:MAX protein, human; C584050:MGA protein, human; C084108:SMARCA4 protein, human