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

Yong Tao, Byunghak Kang, Daniel A. Petkovich, Yuba R. Bhandari, Julie In, Genevieve Stein-O'Brien, Xiangqian Kong, Wenbing Xie, Nicholas Zachos, Shinji Maegawa, Himani Vaidya, Stephen Brown, Ray Whay Chiu Yen, Xiaojian Shao, Jai Thakor, Zhihao Lu, Yi Cai, Yuezheng Zhang, Izaskun Mallona, Miguel Angel PeinadoCynthia A. Zahnow, Nita Ahuja, Elana Fertig, Jean Pierre Issa, Stephen B. Baylin, Hariharan Easwaran

Research output: Contribution to journalArticle

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 Braf V600E , producing the typical human proximal BRAF V600E -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 Braf V600E -induced transformation. Our studies tightly link aging-like epigenetic abnormalities to intestinal cell fate changes and predisposition to oncogene-driven colon tumorigenesis.

Original languageEnglish (US)
Pages (from-to)315-328.e6
JournalCancer cell
Volume35
Issue number2
DOIs
StatePublished - Feb 11 2019

    Fingerprint

Keywords

  • aging
  • BRAF
  • cancer risk
  • CIMP
  • colon adenocarcinomas
  • CpG-island DNA methylation
  • epigenetic silencing
  • transformation
  • tumor predisposition
  • tumorigenesis

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Tao, Y., Kang, B., Petkovich, D. A., Bhandari, Y. R., In, J., Stein-O'Brien, G., Kong, X., Xie, W., Zachos, N., Maegawa, S., Vaidya, H., Brown, S., Chiu Yen, R. W., Shao, X., Thakor, J., Lu, Z., Cai, Y., Zhang, Y., Mallona, I., ... Easwaran, H. (2019). Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and Braf V600E -Induced Tumorigenesis Cancer cell, 35(2), 315-328.e6. https://doi.org/10.1016/j.ccell.2019.01.005