Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and Braf V600E-Induced Tumorigenesis

Cancer Cell. 2019 Feb 11;35(2):315-328.e6. doi: 10.1016/j.ccell.2019.01.005.

Abstract

We addressed the precursor role of aging-like spontaneous promoter DNA hypermethylation in initiating tumorigenesis. Using mouse colon-derived organoids, we show that promoter hypermethylation spontaneously arises in cells mimicking the human aging-like phenotype. The silenced genes activate the Wnt pathway, causing a stem-like state and differentiation defects. These changes render aged organoids profoundly more sensitive than young ones to transformation by BrafV600E, producing the typical human proximal BRAFV600E-driven colon adenocarcinomas characterized by extensive, abnormal gene-promoter CpG-island methylation, or the methylator phenotype (CIMP). Conversely, CRISPR-mediated simultaneous inactivation of a panel of the silenced genes markedly sensitizes to BrafV600E-induced transformation. Our studies tightly link aging-like epigenetic abnormalities to intestinal cell fate changes and predisposition to oncogene-driven colon tumorigenesis.

Keywords: BRAF(V600E); CIMP; CpG-island DNA methylation; aging; cancer risk; colon adenocarcinomas; epigenetic silencing; transformation; tumor predisposition; tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / enzymology
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Age Factors
  • Aging / genetics*
  • Aging / metabolism
  • Aging / pathology
  • Animals
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / pathology
  • DNA Methylation*
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing*
  • Genetic Predisposition to Disease
  • Humans
  • Mice, Inbred NOD
  • Mice, Mutant Strains
  • Mice, SCID
  • Mutation*
  • Phenotype
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins B-raf / metabolism
  • Stem Cells / enzymology*
  • Stem Cells / pathology
  • Time Factors
  • Tissue Culture Techniques
  • Wnt Signaling Pathway / genetics*

Substances

  • BRAF protein, human
  • Braf protein, mouse
  • Proto-Oncogene Proteins B-raf