Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and BrafV600E-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 Peinado; Cynthia A Zahnow; Nita Ahuja; Elana Fertig; Jean-Pierre Issa; Stephen B Baylin; Hariharan Easwaran

doi:10.1016/j.ccell.2019.01.005

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.

Authors

Yong Tao¹, Byunghak Kang¹, Daniel A Petkovich¹, Yuba R Bhandari¹, Julie In², Genevieve Stein-O'Brien³, Xiangqian Kong¹, Wenbing Xie¹, Nicholas Zachos², Shinji Maegawa⁴, Himani Vaidya⁵, Stephen Brown¹, Ray-Whay Chiu Yen¹, Xiaojian Shao⁶, Jai Thakor¹, Zhihao Lu⁷, Yi Cai¹, Yuezheng Zhang⁸, Izaskun Mallona⁹, Miguel Angel Peinado⁹, Cynthia A Zahnow¹, Nita Ahuja¹, Elana Fertig³, Jean-Pierre Issa⁵, Stephen B Baylin¹⁰, Hariharan Easwaran¹¹

Affiliations

¹ CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA.
² Hopkins Conte Digestive Disease, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
³ Division of Biostatistics & Bioinformatics, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁴ Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Unit 853, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
⁵ Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19122, USA.
⁶ Department of Human Genetics, Canadian Centre for Computational Genomics, McGill University, Montreal, QC, Canada.
⁷ Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China.
⁸ Department of Pathology, University of Washington, Seattle, WA 98195, USA.
⁹ Germans Trias i Pujol Health Science Research Institute (IGTP), Program for Personalized Medicine of Cancer, Badalona, 08916 Catalonia, Spain.
¹⁰ CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA. Electronic address: sbaylin1@jhmi.edu.
¹¹ CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA. Electronic address: heaswar1@jhmi.edu.

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.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding