Open AccessV600E Braf induces gastrointestinal crypt senescence and promotes tumour progression through enhanced CpG methylation of p16 INK4a
Author(s) -
Carragher Linda A. S.,
Snell Kimberley R.,
Giblett Susan M.,
Aldridge Victoria S. S.,
Patel Bipin,
Cook Simon J.,
Winton Doug J.,
Marais Richard,
Pritchard Catrin A.
Publication year - 2010
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201000099
Subject(s) - crypt , cpg site , cancer research , methylation , dna methylation , senescence , biology , microbiology and biotechnology , dna , genetics , gene , gene expression , endocrinology
The majority of human colorectal cancers (CRCs) are initiated by mutations arising in the adenomatous polyposis coli (APC) tumour suppressor gene. However, a new class of non‐ APC mutated CRCs has been defined that have a serrated histopathology and carry the V600E BRAF oncogene. Here we have investigated the pathogenesis of serrated CRCs by expressing V600E Braf in the proliferative cells of the mouse gastrointestinal tract. We show that the oncogene drives an initial burst of Mek‐dependent proliferation, leading to the formation of hyperplastic crypts. This is associated with β‐catenin nuclear localization by a mechanism involving Mapk/Erk kinase (Mek)‐dependent, Akt‐independent phosphorylation of Gsk3β. However, hyperplastic crypts remain dormant for prolonged periods due to the induction of crypt senescence accompanied by upregulation of senescence‐associated β‐galactosidase and p16 Ink4a . We show that tumour progression is associated with down‐regulation of p16 Ink4a through enhanced CpG methylation of exon 1 and knockout of Cdkn2a confirms this gene is a barrier to tumour progression. Our studies identify V600E BRAF as an early genetic driver mutation in serrated CRCs and indicate that, unlike APC ‐mutated cancers, this subtype arises by the bypassing of a V600E Braf driven oncogene‐induced senescence programme.