BioProject

Approximately 10% of human colorectal cancer (CRC) are associated with activated BRAFV600E mutation, typically in absence of APC mutation and often associated with a CpG Island Methylator Phenotype (CIMP) phenotype. More...

Approximately 10% of human colorectal cancer (CRC) are associated with activated BRAFV600E mutation, typically in absence of APC mutation and often associated with a CpG Island Methylator Phenotype (CIMP) phenotype. To protect from cancer, normal intestinal epithelial cells are thought to respond to oncogenic BRAFV600E by activation of intrinsic p53 and p16-dependent tumor suppressor mechanisms, such as cellular senescence. Conversely, CIMP is thought to contribute to bypass of these tumor suppressor mechanisms, e.g. via epigenetic silencing of tumor suppressor genes, such as p16. It has been repeatedly proposed that DNMT3B is responsible for BRAFV600E-induced CIMP in human CRC. Here we set out to test this by multiple approaches. By analysis of human TCGA data, we confirmed that expression of DNMT3B is frequently upregulated in CRC and this is often linked to amplification of the DNMT3B gene. In vitro, we found that ectopic expression of DNMT3B antagonizes BRAFV600E-induced proliferation arrest and inflammatory gene expression, two hallmarks of the tumor suppressive senescence program triggered by oncogenes in primary cells. Moreover, DNMT3B over expression decreased survival in a mouse model of BRAFV600E-induced intestinal cancer. However, in primary human cells in vitro, activated BRAFV600E repressed expression of DNMT3B and failed to induce a CIMP phenotype. Finally, a closer analysis of human TCGA data revealed that BRAFV600E mutations and CIMP are both linked to a low expression of DNMT3B. We conclude that while both BRAFV600E and DNMT3B both harbor oncogenic potential in vitro and in vivo and show some evidence of cooperation in tumour promotion, they do not frequently cooperate to promote CIMP and human intestinal cancer. Overall design: Epigenetic profiling by whole genome bisulfite sequencing of BRAF oncogene induced senescent fibroblasts with controls. Less...