Loss of Apc Rapidly Impairs DNA Methylation Programs and Cell Fate Decisions in Lgr5 Intestinal Stem Cells.
Fiche publication
Date publication
juin 2020
Journal
Cancer research
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BARDET Anaïs, Dr WEBER Mickaël
Tous les auteurs :
Bruschi M, Garnier L, Cleroux E, Giordano A, Dumas M, Bardet AF, Kergrohen T, Quesada S, Cesses P, Weber M, Gerbe F, Jay P
Lien Pubmed
Résumé
Colorectal cancer initiation and progression result from the accumulation of genetic and epigenetic alterations. Although aberrant gene expression and DNA methylation profiles are considered hallmarks of colorectal cancer development, the precise timing at which these are produced during tumor establishment remains elusive. Here we investigated the early transcriptional and epigenetic changes induced by adenomatous polyposis coli () inactivation in intestinal crypts. Hyperactivation of the Wnt pathway via inactivation in crypt base columnar intestinal stem cells (ISC) led to their rapid accumulation driven by an impaired molecular commitment to differentiation, which was associated with discrete alterations in DNA methylation. Importantly, inhibiting the enzymes responsible for DNA methylation restored the responsiveness of -deficient intestinal organoids to stimuli regulating the proliferation-to-differentiation transition in ISC. This work reveals that early DNA methylation changes play critical roles in the establishment of the impaired fate decision program consecutive to loss of function. SIGNIFICANCE: This study demonstrates the functional impact of changes in DNA methylation to determine the colorectal cancer cell phenotype following loss of function.
Mots clés
Adenomatous Polyposis Coli Protein, deficiency, Animals, Cell Differentiation, physiology, Cell Division, physiology, Colorectal Neoplasms, genetics, DNA Methylation, DNA Modification Methylases, genetics, Gene Silencing, Intestine, Small, cytology, Mice, Mice, Inbred C57BL, Receptors, G-Protein-Coupled, biosynthesis, Stem Cells, metabolism, Wnt Signaling Pathway
Référence
Cancer Res. 2020 06 1;80(11):2101-2113