EGFR Mutation Induces Transcriptional and Epigenetic Remodeling in GBM

EGFR amplifications or mutations, such as the ligand-independent activated mutation EGFRvIII, promote tumorigenesis in the majority of glioblastomas (GBM). However, the effect of EGFR mutations on the epigenetic and transcriptional programs in cancer cells is not well understood. Liu, Hon, and colleagues identified a set of active enhancers in GBM characterized by histone H3 lysine 4 monomethylation (H3K4me1) and H3K27 acetylation (H3K27ac) and activated by EGFRvIII. Motifs for SOX and forkhead box (FOX) family transcription factors were among the most enriched motifs within these EGFRvIII-activated enhancers. Further, expression of SOX9 and FOXG1 was increased by EGFRvIII in a kinase-dependent manner. SOX9 and FOXG1 bound to EGFRvIII-responsive enhancers, including FOXF1 and TFP2c, as well as to their own enhancers. Analysis of data from The Cancer Genome Atlas revealed that SOX9 and FOXG1 expression was highly correlated with EGFR amplification and mutation in GBMs. H3K4me1 and H3K27ac chromatin immunoprecipitation sequencing in GBMs compared with normal brain identified two clusters of growth factor–associated enhancers that were enriched for SOX and FOX family transcription factor binding and were located near genes differentially expressed in EGFRvIII and wild-type EGFR GBMs. Knockdown of SOX9 or FOXG1 decreased H3K27ac and H3K4me1 at EGFRvIII-responsive enhancers and reduced tumor growth both in vitro and in vivo. Consistent with this finding, SOX9 and FOXG1 regulated genes associated with glioma, including c-MYC target genes. MYC expression, which is regulated by the bromodomain and extraterminal domain (BET) protein BRD4, correlated with SOX9 and FOXG1 expression in GBM, suggesting a potential role for BET inhibitors in treating GBM. Indeed, EGFRvIII-positive GBM cells were found to have an increased sensitivity to the BET inhibitor JQ1, which was mediated by SOX9 and FOXG1. Together, these results indicate that the EGFRvIII mutation alters the transcriptional and epigenetic landscapes of GBM, and suggest that epigenetic therapies may be effective in these tumors.

Liu F, Hon GC, Villa GR, Turner KM, Ikegami S, Yang H, et al. EGFR mutation promotes glioblastoma through epigenome and transcription factor network remodeling. Mol Cell 2015 Oct 8 [Epub ahead of print].