title: Negative regulation of DNMT3A de novo DNA methylation by frequently overexpressed UHRF family proteins as a mechanism for widespread DNA hypomethylation in cancer.
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.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai, China.
authors.forename: Yuanhui
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai, China.
authors.forename: Pishun
authors.initials: P
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Fang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai, China.
authors.forename: Haijun
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai, China.
authors.forename: Liangliang
authors.initials: L
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Hao
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai, China.
authors.forename: Junying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University , Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai, China.
authors.forename: Jialun
authors.initials: J
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai, China.
authors.forename: Ruiping
authors.initials: R
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai, China.
authors.forename: James X
authors.initials: JX
authors.lastname: Du
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai, China.
authors.forename: Jiwen
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University , Shanghai, China.
authors.forename: Taiping
authors.initials: T
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.affiliation: 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.
authors.forename: Jackie
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center , Smithville, TX, USA.
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Yu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai, China.
authors.forename: Qihan
authors.initials: Q
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Jiemin
authors.initials: J
authors.lastname: Wong
keywords: DNA; DNMT1; DNMT3A; UHRF1; UHRF2; cancer; hypomethylation