MAFG Mediates CIMP in BRAF-Mutant Colorectal Cancer Free

Colorectal cancers are often characterized by extensive DNA hypermethylation of promoter-associated CpG islands, known as the CpG island methylator phenotype (CIMP), which results in transcriptional silencing of many tumor-suppressor and DNA repair genes. High levels of CpG island methylation in colorectal cancers have been associated with an activating mutation in the BRAF oncoprotein and transcriptional inactivation of the DNA mismatch repair gene mutL homolog 1 (MLH1); however, the mechanisms underlying aberrant promoter methylation and generation of CIMP in colorectal cancer are poorly understood. Using a genome-wide RNAi screen, Fang and colleagues identified 16 candidate mediators of MLH1 transcriptional silencing, including the transcriptional repressor MAFG. In BRAF^V600E-positive colorectal cancer cells, MAFG directly bound the MLH1 promoter as a heterodimer with BTB and CNC homology 1 (BACH1) and initiated the recruitment of a corepressor complex containing the chromatin-remodeling factor chromodomain helicase DNA-binding protein 8 (CHD8) and the DNA methyltransferase DNMT3B to facilitate MLH1 promoter hypermethylation and transcriptional silencing. BRAF^V600E signaling promoted ERK-dependent phosphorylation of MAFG, resulting in decreased MAFG ubiquitination and enhanced MAFG protein stability. These results were not specific to BRAF^V600E-mediated ERK activation, but were also observed in EGFR-mutant colorectal cancer cells with enhanced ERK signaling. Importantly, MAFG and its corepressors also mediated the transcriptional silencing of many CIMP marker genes in BRAF^V600E-positive colorectal cancer cells and human tumor samples, and knockdown of MAFG or CHD8 reduced tumor growth, suggesting that the MAFG corepressor complex acts globally to induce CIMP and promote tumorigenesis. Intriguingly, KRAS-mutant colorectal cancer cells exhibited formation of a distinct repressor complex at commonly regulated CIMP gene promoters. These results implicate MAFG as a critical mediator of CIMP in BRAF-mutant colorectal cancer and suggest that oncoproteins directly induce CIMP by selectively promoting the assembly of different corepressor complexes.

Fang M, Ou J, Hutchinson L, Green MR. The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG island methylator phenotype. Mol Cell 2014;55:904–15.