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.
Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and BrafV600E-Induced Tumorigenesis.
Yong Tao,Byunghak Kang,Daniel Petkovich,Y. Bhandari,Julie G. In,Genevieve L. Stein-O’Brien,X. Kong,W. Xie,N. Zachos,S. Maegawa,Himani Vaidya,Stephen M. Brown,Ray-Whay Chiu Yen,Xiaojian Shao,Jai Thakor,Zhihao Lu,Yi Cai,Yuezheng Zhang,I. Mallona,M. Peinado,C. Zahnow,N. Ahuja,E. Fertig,J. Issa,S. Baylin,H. Easwaran
Published 2019 in Cancer Cell
ABSTRACT
PUBLICATION RECORD
- Publication year
2019
- Venue
Cancer Cell
- Publication date
2019-02-01
- Fields of study
Biology, Medicine
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
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