Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties

Xiangqian Kong; Jie Chen; Wenbing Xie; Stephen M. Brown; Yi Cai; Kaichun Wu; Daiming Fan; Yongzhan Nie; Srinivasan Yegnasubramanian; Rochelle L. Tiedemann; Yong Tao; Ray Whay Chiu Yen; Michael J. Topper; Cynthia A. Zahnow; Hariharan Easwaran; Scott B. Rothbart; Limin Xia; Stephen B. Baylin

doi:10.1016/j.ccell.2019.03.003

Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties

Xiangqian Kong, Jie Chen, Wenbing Xie, Stephen M. Brown, Yi Cai, Kaichun Wu, Daiming Fan, Yongzhan Nie, Srinivasan Yegnasubramanian, Rochelle L. Tiedemann, Yong Tao, Ray Whay Chiu Yen, Michael J. Topper, Cynthia A. Zahnow, Hariharan Easwaran, Scott B. Rothbart, Limin Xia, Stephen B. Baylin

School of Medicine

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

28 Scopus citations

Abstract

UHRF1 facilitates the establishment and maintenance of DNA methylation patterns in mammalian cells. The establishment domains are defined, including E3 ligase function, but the maintenance domains are poorly characterized. Here, we demonstrate that UHRF1 histone- and hemimethylated DNA binding functions, but not E3 ligase activity, maintain cancer-specific DNA methylation in human colorectal cancer (CRC) cells. Disrupting either chromatin reader activity reverses DNA hypermethylation, reactivates epigenetically silenced tumor suppressor genes (TSGs), and reduces CRC oncogenic properties. Moreover, an inverse correlation between high UHRF1 and low TSG expression tracks with CRC progression and reduced patient survival. Defining critical UHRF1 domain functions and its relationship with CRC prognosis suggests directions for, and value of, targeting this protein to develop therapeutic DNA demethylating agents.

Original language	English (US)
Pages (from-to)	633-648.e7
Journal	Cancer cell
Volume	35
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2019.03.003
State	Published - Apr 15 2019

Keywords

UHRF1
colorectal cancer prognosis
domain functions
maintenance DNA methylation
next-generation DNA demethylating agents
oncogenic properties
tumor suppressor gene silencing

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2019.03.003

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Kong, X., Chen, J., Xie, W., Brown, S. M., Cai, Y., Wu, K., Fan, D., Nie, Y., Yegnasubramanian, S., Tiedemann, R. L., Tao, Y., Chiu Yen, R. W., Topper, M. J., Zahnow, C. A., Easwaran, H., Rothbart, S. B., Xia, L., & Baylin, S. B. (2019). Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties. Cancer cell, 35(4), 633-648.e7. https://doi.org/10.1016/j.ccell.2019.03.003

Kong, X, Chen, J, Xie, W, Brown, SM, Cai, Y, Wu, K, Fan, D, Nie, Y, Yegnasubramanian, S, Tiedemann, RL, Tao, Y, Chiu Yen, RW , Topper, MJ , Zahnow, CA , Easwaran, H, Rothbart, SB, Xia, L & Baylin, SB 2019, 'Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties', Cancer cell, vol. 35, no. 4, pp. 633-648.e7. https://doi.org/10.1016/j.ccell.2019.03.003

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abstract = "UHRF1 facilitates the establishment and maintenance of DNA methylation patterns in mammalian cells. The establishment domains are defined, including E3 ligase function, but the maintenance domains are poorly characterized. Here, we demonstrate that UHRF1 histone- and hemimethylated DNA binding functions, but not E3 ligase activity, maintain cancer-specific DNA methylation in human colorectal cancer (CRC) cells. Disrupting either chromatin reader activity reverses DNA hypermethylation, reactivates epigenetically silenced tumor suppressor genes (TSGs), and reduces CRC oncogenic properties. Moreover, an inverse correlation between high UHRF1 and low TSG expression tracks with CRC progression and reduced patient survival. Defining critical UHRF1 domain functions and its relationship with CRC prognosis suggests directions for, and value of, targeting this protein to develop therapeutic DNA demethylating agents.",

keywords = "UHRF1, colorectal cancer prognosis, domain functions, maintenance DNA methylation, next-generation DNA demethylating agents, oncogenic properties, tumor suppressor gene silencing",

author = "Xiangqian Kong and Jie Chen and Wenbing Xie and Brown, {Stephen M.} and Yi Cai and Kaichun Wu and Daiming Fan and Yongzhan Nie and Srinivasan Yegnasubramanian and Tiedemann, {Rochelle L.} and Yong Tao and {Chiu Yen}, {Ray Whay} and Topper, {Michael J.} and Zahnow, {Cynthia A.} and Hariharan Easwaran and Rothbart, {Scott B.} and Limin Xia and Baylin, {Stephen B.}",

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AU - Cai, Yi

AU - Wu, Kaichun

AU - Fan, Daiming

AU - Nie, Yongzhan

AU - Yegnasubramanian, Srinivasan

AU - Tiedemann, Rochelle L.

AU - Tao, Yong

AU - Chiu Yen, Ray Whay

AU - Topper, Michael J.

AU - Zahnow, Cynthia A.

AU - Easwaran, Hariharan

AU - Rothbart, Scott B.

AU - Xia, Limin

AU - Baylin, Stephen B.

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N2 - UHRF1 facilitates the establishment and maintenance of DNA methylation patterns in mammalian cells. The establishment domains are defined, including E3 ligase function, but the maintenance domains are poorly characterized. Here, we demonstrate that UHRF1 histone- and hemimethylated DNA binding functions, but not E3 ligase activity, maintain cancer-specific DNA methylation in human colorectal cancer (CRC) cells. Disrupting either chromatin reader activity reverses DNA hypermethylation, reactivates epigenetically silenced tumor suppressor genes (TSGs), and reduces CRC oncogenic properties. Moreover, an inverse correlation between high UHRF1 and low TSG expression tracks with CRC progression and reduced patient survival. Defining critical UHRF1 domain functions and its relationship with CRC prognosis suggests directions for, and value of, targeting this protein to develop therapeutic DNA demethylating agents.

AB - UHRF1 facilitates the establishment and maintenance of DNA methylation patterns in mammalian cells. The establishment domains are defined, including E3 ligase function, but the maintenance domains are poorly characterized. Here, we demonstrate that UHRF1 histone- and hemimethylated DNA binding functions, but not E3 ligase activity, maintain cancer-specific DNA methylation in human colorectal cancer (CRC) cells. Disrupting either chromatin reader activity reverses DNA hypermethylation, reactivates epigenetically silenced tumor suppressor genes (TSGs), and reduces CRC oncogenic properties. Moreover, an inverse correlation between high UHRF1 and low TSG expression tracks with CRC progression and reduced patient survival. Defining critical UHRF1 domain functions and its relationship with CRC prognosis suggests directions for, and value of, targeting this protein to develop therapeutic DNA demethylating agents.

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Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties

Abstract

Keywords

ASJC Scopus subject areas

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