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, S Yegnasubramanian, Rochelle L. Tiedemann, Yong Tao, Ray-Whay Yen, Michael J. Topper, Cynthia Zahnow, Hariharan Easwaran, Scott B. Rothbart, Limin Xia, Stephen B Baylin

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)633-648.e7
JournalCancer cell
Volume35
Issue number4
DOIs
StatePublished - Apr 15 2019

Fingerprint

DNA Methylation
Colonic Neoplasms
Colorectal Neoplasms
Ubiquitin-Protein Ligases
Tumor Suppressor Genes
DNA
Maintenance
Protein Transport
Histones
Chromatin
Gene Expression
Survival
Neoplasms
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties. / Kong, Xiangqian; Chen, Jie; Xie, Wenbing; Brown, Stephen M.; Cai, Yi; Wu, Kaichun; Fan, Daiming; Nie, Yongzhan; Yegnasubramanian, S; Tiedemann, Rochelle L.; Tao, Yong; Yen, Ray-Whay; Topper, Michael J.; Zahnow, Cynthia; Easwaran, Hariharan; Rothbart, Scott B.; Xia, Limin; Baylin, Stephen B.

In: Cancer cell, Vol. 35, No. 4, 15.04.2019, p. 633-648.e7.

Research output: Contribution to journalArticle

Kong, Xiangqian ; Chen, Jie ; Xie, Wenbing ; Brown, Stephen M. ; Cai, Yi ; Wu, Kaichun ; Fan, Daiming ; Nie, Yongzhan ; Yegnasubramanian, S ; Tiedemann, Rochelle L. ; Tao, Yong ; Yen, Ray-Whay ; Topper, Michael J. ; Zahnow, Cynthia ; Easwaran, Hariharan ; Rothbart, Scott B. ; Xia, Limin ; Baylin, Stephen B. / Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties. In: Cancer cell. 2019 ; Vol. 35, No. 4. pp. 633-648.e7.
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