title: The tumour suppressor and chromatin-remodelling factor BRG1 antagonizes Myc activity and promotes cell differentiation in human cancer.
abstract: BRG1, a member of the SWI/SNF complex, is mutated in cancer, but it is unclear how it promotes tumourigenesis. We report that re-expression of BRG1 in lung cancer cells up-regulates lung-specific transcripts, restoring the gene expression signature of normal lung. Using cell lines from several cancer types we found that those lacking BRG1 do not respond to retinoic acid (RA) or glucocorticoids (GC), while restoration of BRG1 restores sensitivity. Conversely, in SH-SY5Y cells, a paradigm of RA-dependent differentiation, abrogation of BRG1 prevented the response to RA. Further, our data suggest an antagonistic functional connection between BRG1 and MYC, whereby, refractoriness to RA and GC by BRG1 inactivation involves deregulation of MYC activity. Mechanistically, some of these effects are mediated by BRG1 binding to MYC and MYC-target promoters. The BRG1-MYC antagonism was also evident in primary tumours. Finally, BRG1 restoration significantly dampened invasion and progression and decreased MYC in lung cancer cells orthotopically implanted in nude mice. Thus, BRG1 inactivation enables cancer cells to sustain undifferentiated gene expression programs and prevent its response to environmental stimuli.
authors.affiliation: Genes and Cancer Group, Cancer Epigenetics and Biology Program-PEBC, Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Octavio A
authors.initials: OA
authors.lastname: Romero
authors.forename: Fernando
authors.initials: F
authors.lastname: Setien
authors.forename: Sam
authors.initials: S
authors.lastname: John
authors.forename: Pol
authors.initials: P
authors.lastname: Gimenez-Xavier
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gómez-López
authors.forename: David
authors.initials: D
authors.lastname: Pisano
authors.forename: Enric
authors.initials: E
authors.lastname: Condom
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Hager
authors.forename: Montse
authors.initials: M
authors.lastname: Sanchez-Cespedes
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D005938:Glucocorticoids; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D014212:Tretinoin; C084108:SMARCA4 protein, human; D004265:DNA Helicases