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

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2019 Feb 13

PMID 30753828

Citations 93

Authors

Yong Tao

Byunghak Kang

Daniel A Petkovich

Yuba R Bhandari

Julie In

Genevieve Stein-OBrien

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

Affiliations

Soon will be listed here.

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

Citing Articles

Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy.

Bai W, Xu J, Gu W, Wang D, Cui Y, Rong W Nat Commun. 2025; 16(1):474.

PMID: 39774694 PMC: 11707192. DOI: 10.1038/s41467-024-55481-7.

Epigenetics-targeted drugs: current paradigms and future challenges.

Dai W, Qiao X, Fang Y, Guo R, Bai P, Liu S Signal Transduct Target Ther. 2024; 9(1):332.

PMID: 39592582 PMC: 11627502. DOI: 10.1038/s41392-024-02039-0.

DNA Methylation Classes of Stage II and III Primary Melanomas and Their Clinical and Prognostic Significance.

Conway K, Edmiston S, Vondras A, Reiner A, Corcoran D, Shen R JCO Precis Oncol. 2024; 8:e2400375.

PMID: 39509669 PMC: 11737429. DOI: 10.1200/PO-24-00375.

Emerging strategies to investigate the biology of early cancer.

Zhou R, Tang X, Wang Y Nat Rev Cancer. 2024; 24(12):850-866.

PMID: 39433978 DOI: 10.1038/s41568-024-00754-y.

Three-Dimensional Cell Cultures as a Feasible and Promising Alternative to Two-Dimensional and Animal Models in Cancer Research.

Esposito A, Ferraresi A, Vallino L, Garavaglia B, Dhanasekaran D, Isidoro C Int J Biol Sci. 2024; 20(13):5293-5311.

PMID: 39430243 PMC: 11488579. DOI: 10.7150/ijbs.96469.

References

Fang M, Ou J, Hutchinson L, Green M . The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG Island Methylator phenotype. Mol Cell. 2014; 55(6):904-915. PMC: 4170521. DOI: 10.1016/j.molcel.2014.08.010. View

Yamamoto E, Suzuki H, Yamano H, Maruyama R, Nojima M, Kamimae S . Molecular dissection of premalignant colorectal lesions reveals early onset of the CpG island methylator phenotype. Am J Pathol. 2012; 181(5):1847-61. DOI: 10.1016/j.ajpath.2012.08.007. View

Vaz M, Hwang S, Kagiampakis I, Phallen J, Patil A, OHagan H . Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations. Cancer Cell. 2017; 32(3):360-376.e6. PMC: 5596892. DOI: 10.1016/j.ccell.2017.08.006. View

Onuma K, Ochiai M, Orihashi K, Takahashi M, Imai T, Nakagama H . Genetic reconstitution of tumorigenesis in primary intestinal cells. Proc Natl Acad Sci U S A. 2013; 110(27):11127-32. PMC: 3703980. DOI: 10.1073/pnas.1221926110. View

Krueger F, Andrews S . Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinformatics. 2011; 27(11):1571-2. PMC: 3102221. DOI: 10.1093/bioinformatics/btr167. View

Noreen F, Roosli M, Gaj P, Pietrzak J, Weis S, Urfer P . Modulation of age- and cancer-associated DNA methylation change in the healthy colon by aspirin and lifestyle. J Natl Cancer Inst. 2014; 106(7). PMC: 4112799. DOI: 10.1093/jnci/dju161. View

Weeber F, van de Wetering M, Hoogstraat M, Dijkstra K, Krijgsman O, Kuilman T . Preserved genetic diversity in organoids cultured from biopsies of human colorectal cancer metastases. Proc Natl Acad Sci U S A. 2015; 112(43):13308-11. PMC: 4629330. DOI: 10.1073/pnas.1516689112. View

Teschendorff A, Menon U, Gentry-Maharaj A, Ramus S, Weisenberger D, Shen H . Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res. 2010; 20(4):440-6. PMC: 2847747. DOI: 10.1101/gr.103606.109. View

Ahuja N, Li Q, Mohan A, Baylin S, Issa J . Aging and DNA methylation in colorectal mucosa and cancer. Cancer Res. 1998; 58(23):5489-94. View

10.

Issa J . CpG island methylator phenotype in cancer. Nat Rev Cancer. 2004; 4(12):988-93. DOI: 10.1038/nrc1507. View

11.

Easwaran H, Johnstone S, Van Neste L, Ohm J, Mosbruger T, Wang Q . A DNA hypermethylation module for the stem/progenitor cell signature of cancer. Genome Res. 2012; 22(5):837-49. PMC: 3337430. DOI: 10.1101/gr.131169.111. View

12.

Feng Y, Sentani K, Wiese A, Sands E, Green M, Bommer G . Sox9 induction, ectopic Paneth cells, and mitotic spindle axis defects in mouse colon adenomatous epithelium arising from conditional biallelic Apc inactivation. Am J Pathol. 2013; 183(2):493-503. PMC: 3730784. DOI: 10.1016/j.ajpath.2013.04.013. View

13.

Hinoue T, Weisenberger D, Pan F, Campan M, Kim M, Young J . Analysis of the association between CIMP and BRAF in colorectal cancer by DNA methylation profiling. PLoS One. 2009; 4(12):e8357. PMC: 2791229. DOI: 10.1371/journal.pone.0008357. View

14.

Baylin S, Jones P . Epigenetic Determinants of Cancer. Cold Spring Harb Perspect Biol. 2016; 8(9). PMC: 5008069. DOI: 10.1101/cshperspect.a019505. View

15.

Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C . Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006; 444(7119):638-42. DOI: 10.1038/nature05327. View

16.

Sato T, Vries R, Snippert H, van de Wetering M, Barker N, Stange D . Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009; 459(7244):262-5. DOI: 10.1038/nature07935. View

17.

Zetsche B, Gootenberg J, Abudayyeh O, Slaymaker I, Makarova K, Essletzbichler P . Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Cas system. Cell. 2015; 163(3):759-71. PMC: 4638220. DOI: 10.1016/j.cell.2015.09.038. View

18.

Tong K, Pellon-Cardenas O, Sirihorachai V, Warder B, Kothari O, Perekatt A . Degree of Tissue Differentiation Dictates Susceptibility to BRAF-Driven Colorectal Cancer. Cell Rep. 2017; 21(13):3833-3845. PMC: 5747303. DOI: 10.1016/j.celrep.2017.11.104. View

19.

Petkovich D, Podolskiy D, Lobanov A, Lee S, Miller R, Gladyshev V . Using DNA Methylation Profiling to Evaluate Biological Age and Longevity Interventions. Cell Metab. 2017; 25(4):954-960.e6. PMC: 5578459. DOI: 10.1016/j.cmet.2017.03.016. View

20.

Fertig E, Ding J, Favorov A, Parmigiani G, Ochs M . CoGAPS: an R/C++ package to identify patterns and biological process activity in transcriptomic data. Bioinformatics. 2010; 26(21):2792-3. PMC: 3025742. DOI: 10.1093/bioinformatics/btq503. View