DNMT3B Oncogenic Activity in Human Intestinal Cancer Is Not Linked to CIMP or BRAFV600E Mutation

MacKenzie, D. J. et al. (2020) DNMT3B Oncogenic Activity in Human Intestinal Cancer Is Not Linked to CIMP or BRAFV600E Mutation. iScience, 23(2), 100838. (doi: 10.1016/j.isci.2020.100838) (PMID:32058953) (PMCID:PMC7000804)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cruickshanks, Dr Hazel and Blyth, Professor Karen and Robertson, Mr Neil and MacKenzie, Dr Douglas and Adams, Professor Peter and McBryan, Dr Anthony and Reid, Mrs Claire
Authors: MacKenzie, D. J., Robertson, N. A., Rather, I., Reid, C., Sendzikaite, G., Cruickshanks, H., McBryan, T., Hodges, A., Pritchard, C., Blyth, K., and Adams, P. D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:iScience
Publisher:Elsevier (Cell Press)
ISSN:2589-0042
ISSN (Online):2589-0042
Published Online:14 January 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in iScience 23:100838
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
168615Senescence-associated chromatin changes a barrier to tumor progression.Owen SansomCancer Research UK (CRUK)C10652/A16566CS - Epigenetics