DNMT3B Oncogenic Activity in Human Intestinal Cancer Is Not Linked to CIMP or BRAFV600E Mutation
Douglas J. MacKenzie,
Neil A. Robertson,
Iqbal Rather,
Claire Reid,
Gintare Sendzikaite,
Hazel Cruickshanks,
Tony McBryan,
Andrew Hodges,
Catrin Pritchard,
Karen Blyth,
Peter D. Adams
Affiliations
Douglas J. MacKenzie
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
Neil A. Robertson
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
Iqbal Rather
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
Claire Reid
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
Gintare Sendzikaite
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
Hazel Cruickshanks
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
Tony McBryan
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
Andrew Hodges
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
Catrin Pritchard
Leicester Cancer Research Centre, University of Leicester, Leicester, UK
Karen Blyth
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; Cancer Research UK Beatson Institute, Glasgow, UK
Peter D. Adams
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; Corresponding author
Summary: 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 (CIMP) phenotype. To protect from cancer, normal intestinal epithelial cells 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 in silico, in vitro, and in vivo approaches. We conclude that although both BRAFV600E and DNMT3B harbor oncogenic potential in vitro and in vivo and show some evidence of cooperation in tumor promotion, they do not frequently cooperate to promote CIMP and human intestinal cancer. : Biological Sciences; Molecular Biology; Cancer Subject Areas: Biological Sciences, Molecular Biology, Cancer
