Open AccessThe tumour suppressor and chromatin‐remodelling factor BRG1 antagonizes Myc activity and promotes cell differentiation in human cancer
Author(s) -
Romero Octavio A.,
Setien Fernando,
John Sam,
GimenezXavier Pol,
GómezLópez Gonzalo,
Pisano David,
Condom Enric,
Villanueva Alberto,
Hager Gordon L.,
SanchezCespedes Montse
Publication year - 2012
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201200236
Subject(s) - cancer research , lung cancer , retinoic acid , swi/snf , chromatin remodeling , transcription factor , cancer , suppressor , cancer cell , biology , immunology , microbiology and biotechnology , gene , medicine , genetics
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.