Negative regulation of DNMT3A de novo DNA methylation by frequently overexpressed UHRF family proteins as a mechanism for widespread DNA hypomethylation in cancer

Yuanhui Jia; Pishun Li; Lan Fang; Haijun Zhu; Liangliang Xu; Hao Cheng; Junying Zhang; Fei Li; Yan Feng; Yan Li; Jialun Li; Ruiping Wang; James X Du; Jiwen Li; Taiping Chen; Hongbin Ji; Jackie Han; Wenqiang Yu; Qihan Wu; Jiemin Wong

doi:10.1038/celldisc.2016.7

Negative regulation of DNMT3A de novo DNA methylation by frequently overexpressed UHRF family proteins as a mechanism for widespread DNA hypomethylation in cancer

Cell Discov. 2016 Apr 12:2:16007. doi: 10.1038/celldisc.2016.7. eCollection 2016.

Authors

Yuanhui Jia¹, Pishun Li¹, Lan Fang¹, Haijun Zhu¹, Liangliang Xu¹, Hao Cheng², Junying Zhang¹, Fei Li³, Yan Feng³, Yan Li⁴, Jialun Li¹, Ruiping Wang¹, James X Du¹, Jiwen Li¹, Taiping Chen⁴, Hongbin Ji³, Jackie Han², Wenqiang Yu⁵, Qihan Wu¹, Jiemin Wong⁶

Affiliations

¹ Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai, China.
² Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai, China.
³ Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; CAS center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
⁴ Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University , Shanghai, China.
⁵ Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center , Smithville, TX, USA.
⁶ Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.

Abstract

Global DNA hypomethylation is a most common epigenetic alteration in cancer, but the mechanism remains elusive. Previous studies demonstrate that UHRF1 but not UHRF2 is required for mediating DNA maintenance methylation by DNMT1. Here we report unexpectedly a conserved function for UHRF1 and UHRF2: inhibiting de novo DNA methylation by functioning as E3 ligases promoting DNMT3A degradation. UHRF1/2 are frequently overexpressed in cancers and we present evidence that UHRF1/2 overexpression downregulates DNMT3A proteins and consequently leads to DNA hypomethylation. Abrogating this negative regulation on DNMT3A or overexpression of DNMT3A leads to increased DNA methylation and impaired tumor growth. We propose a working model that UHRF1/2 safeguards the fidelity of DNA methylation and suggests that UHRF1/2 overexpression is likely a causal factor for widespread DNA hypomethylation in cancer via suppressing DNMT3A.

Keywords: DNA; DNMT1; DNMT3A; UHRF1; UHRF2; cancer; hypomethylation.