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

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

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 language	English (US)
Pages (from-to)	315-328.e6
Journal	Cancer cell
Volume	35
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2019.01.005
State	Published - Feb 11 2019

Keywords

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

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1016/j.ccell.2019.01.005

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

Tao, Y, Kang, B, Petkovich, DA, Bhandari, YR, In, J, Stein-O'Brien, G, Kong, X, Xie, W, Zachos, N, Maegawa, S, Vaidya, H, Brown, S, Chiu Yen, RW, Shao, X, Thakor, J, Lu, Z, Cai, Y, Zhang, Y, Mallona, I, Peinado, MA, Zahnow, CA, Ahuja, N, Fertig, E, Issa, JP, Baylin, SB & Easwaran, H 2019, 'Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and Braf^V600E-Induced Tumorigenesis', Cancer cell, vol. 35, no. 2, pp. 315-328.e6. https://doi.org/10.1016/j.ccell.2019.01.005

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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.",

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AU - Bhandari, Yuba R.

AU - In, Julie

AU - Stein-O'Brien, Genevieve

AU - Kong, Xiangqian

AU - Xie, Wenbing

AU - Zachos, Nicholas

AU - Maegawa, Shinji

AU - Vaidya, Himani

AU - Brown, Stephen

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AU - Lu, Zhihao

AU - Cai, Yi

AU - Zhang, Yuezheng

AU - Mallona, Izaskun

AU - Peinado, Miguel Angel

AU - Zahnow, Cynthia A.

AU - Ahuja, Nita

AU - Fertig, Elana

AU - Issa, Jean Pierre

AU - Baylin, Stephen B.

AU - Easwaran, Hariharan

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