The tumour suppressor and chromatin‐remodelling factor BRG1 antagonizes Myc activity and promotes cell differentiation in human cancer

EMBO Molecular Medicine

Octavio A. Romero³  Fernando Setien³  Sam John²  Pol Gimenez-Xavier³  Gonzalo Gómez-López¹  David Pisano¹  Enric Condom⁵  Alberto Villanueva⁴  Gordon L. Hager² 

[1] Bioinformatics Unit, Structural Biology and BioComputing Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain;Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;Genes and Cancer Group, Cancer Epigenetics and Biology Program-PEBC, Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain;Translational Research Laboratory, Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain;Pathology Department, Bellvitge Hospital, Hospitalet de Llobregat, Barcelona, Spain

关键词: BRG1;    lung cancer;    MYC;    retinoic acid;    SWI/SNF;   

DOI  :  10.1002/emmm.201200236

来源: Wiley

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2012 EMBO Molecular Medicine