TY - JOUR
T1 - Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties
AU - Kong, Xiangqian
AU - Chen, Jie
AU - Xie, Wenbing
AU - Brown, Stephen M.
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.
N1 - Funding Information:
Research was supported by grants from the National Key Research and Development Program of China 2018YFC1312103 (to L.X.), National Natural Science Foundation of China no. 81522031 (to L.X.), and no. 81772623 (to L.X.), National Institute of Environmental Health Sciences, National Institutes of Health (R01ES011858) (to S.B.B.), NIH R35GM124736 (to S.B.R.), and the American Cancer Society PF1624501DMC (to R.L.T.). Research was also supported by The Hodson Trust (to S.B.B.) and The Commonwealth Foundation (to S.B.B.). S.B.B. is an inventor of MSP which is licensed to MDxHealth in agreement with Johns Hopkins University (to J.H.U.). S.B.B. and J.H.U. are entitled to royalty sale shares. We acknowledge the help of Dr. Ioannis Kagiampakis in generating the enhancer probes for methylation EPIC array analysis, and the help of Dr. Lijing Yang and Dr. Michelle Vaz for animal experiments. The graphical abstract was created with BioRender. Studies utilized the Johns Hopkins SKCC Microarray Core (P30CA006973) and Bloomberg Flow Cytometry and Immunology Cores. X.K. J.C. W.X. S.B.R. L.X. and S.B.B. designed the experiments, performed data analyses, and wrote the manuscript. X.K. and J.C. performed the experiments. W.X. and X.K. performed bioinformatics analyses. S.M.B. Y.T. and C.A.Z. helped with mouse experiments. Y.C. K.W. D.F. Y.N. S.Y. R.L.T. R.-W.C.Y. H.E. and M.J.T. assisted with discussions and analyses. The authors declare no competing interests.
Funding Information:
Research was supported by grants from the National Key Research and Development Program of China 2018YFC1312103 (to L.X.), National Natural Science Foundation of China no. 81522031 (to L.X.), and no. 81772623 (to L.X.), National Institute of Environmental Health Sciences , National Institutes of Health ( R01ES011858 ) (to S.B.B.), NIH R35GM124736 (to S.B.R.), and the American Cancer Society PF1624501DMC (to R.L.T.). Research was also supported by The Hodson Trust (to S.B.B.) and The Commonwealth Foundation (to S.B.B.). S.B.B. is an inventor of MSP which is licensed to MDxHealth in agreement with Johns Hopkins University (to J.H.U.). S.B.B. and J.H.U. are entitled to royalty sale shares. We acknowledge the help of Dr. Ioannis Kagiampakis in generating the enhancer probes for methylation EPIC array analysis, and the help of Dr. Lijing Yang and Dr. Michelle Vaz for animal experiments. The graphical abstract was created with BioRender. Studies utilized the Johns Hopkins SKCC Microarray Core (P30CA006973) and Bloomberg Flow Cytometry and Immunology Cores.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/4/15
Y1 - 2019/4/15
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.
KW - UHRF1
KW - colorectal cancer prognosis
KW - domain functions
KW - maintenance DNA methylation
KW - next-generation DNA demethylating agents
KW - oncogenic properties
KW - tumor suppressor gene silencing
UR - http://www.scopus.com/inward/record.url?scp=85064085680&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064085680&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2019.03.003
DO - 10.1016/j.ccell.2019.03.003
M3 - Article
C2 - 30956060
AN - SCOPUS:85064085680
SN - 1535-6108
VL - 35
SP - 633-648.e7
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -