BRAF^V600E maintains the CpG island methylator phenotype, and DNA methylation of PRC2 targets genes in colon cancer

In colon cancer, the BRAF^V600E mutation is strongly associated with the CpG island methylator phenotype (CIMP). Here, we characterized the contribution of BRAF^V600E to maintenance of aberrant DNA methylation using CRISPR-LbCpf1-corrected BRAF (V600E) organoids. DNA methylation analyses identified 5,187 differentially methylated CpGs within CpG islands—82% hypermethylated in BRAF^V600E organoids—including CIMP-associated genes and polycomb repressor complex 2 (PRC2) target genes. RNA sequencing showed concordant repression of these genes. Furthermore, BRAF^V600E organoids demonstrated high expression of PRC2 core components (EZH2, SUZ12, and EED), showed PRC2-induced H3K27 trimethylation in promoter regions, and maintained a PRC2-associated embryonic phenotype. This phenotype was lost following mutation correction or DNA methylation inhibition. These findings show that BRAF^V600E maintains aberrant DNA and histone methylation patterns in advanced colon cancer, likely preserving the transformed phenotype. Silencing of PRC2 target genes may contribute to this phenomenon. Epigenetic therapies may have value in the treatment of BRAF^V600E-mutant colon cancer.