title: GSK3β inactivation promotes the oncogenic functions of EZH2 and enhances methylation of H3K27 in human breast cancers.
abstract: During the process of tumorigenesis, inactivation of tumor suppressors is a critical step. EZH2, a histone methyltransferase, promotes cell growth and migration through catalyzing trimethylation of histone H3 at Lys 27 (H3K27me3) and plays an important role in tumorigenesis. Its expression can be controlled by phosphorylation. However, the regulation of EZH2 activity by tumor suppressor kinase is not well understood. In this study, we show that glycogen synthase kinase 3 beta (GSK3β) negatively regulates H3K27 trimethylation. We also validate that GSKβ physically interacts with EZH2, and their interaction occurs in the cytosol. GSK3β phosphorylates EZH2 at Ser363 and Thr367 in vitro, and activating GSK3β upregulates Thr367 phosphorylationin vivo. Cells expressing GSK3β-non-phosphorylatable mutant EZH2 have higher H3K27 trimethylation and enhanced ability of cell migration and anchorage-independent growth. Inactivation of GSK3β as measured by its phosphorylation at Ser9 is positively correlated with higher level of H3K27 trimethylation in tumor tissues from breast cancer patients. Our study indicated that GSK3β phosphorylates EZH2 at Ser363 and Thr367, resulting in reduced H3K27 trimethylation and biological activity of EZH2 in breast cancer.
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.|Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 333, Taiwan.
authors: How-Wen
authors: HW
authors: Ko
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.
authors: Heng-Huan
authors: HH
authors: Lee
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Longfei
authors: L
authors: Huo
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Weiya
authors: W
authors: Xia
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.|Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei 112, Taiwan.
authors: Cheng-Chieh
authors: CC
authors: Yang
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.|Department of Biotechnology, Asia University, Taichung 413, Taiwan.
authors: Jennifer L
authors: JL
authors: Hsu
authors: Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.|Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan.
authors: Long-Yuan
authors: LY
authors: Li
authors: Institute of Molecular Biology, National Chung Hsing University, Taichung 402, Taiwan.
authors: Chien-Chen
authors: CC
authors: Lai
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.
authors: Li-Chuan
authors: LC
authors: Chan
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Chien-Chia
authors: CC
authors: Cheng
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.
authors: Adam M
authors: AM
authors: Labaff
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.
authors: Hsin-Wei
authors: HW
authors: Liao
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Seung-Oe
authors: SO
authors: Lim
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Chia-Wei
authors: CW
authors: Li
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Yongkun
authors: Y
authors: Wei
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Lei
authors: L
authors: Nie
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Hirohito
authors: H
authors: Yamaguchi
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.|Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.|Department of Biotechnology, Asia University, Taichung 413, Taiwan.
authors: Mien-Chie
authors: MC
authors: Hung
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D002384:Catalysis; D045744:Cell Line, Tumor; D002465:Cell Movement; D003600:Cytosol / Q000378:metabolism; D019175:DNA Methylation; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006657:Histones / Q000737:chemistry*; D006801:Humans; D009154:Mutation; D009857:Oncogenes; D010766:Phosphorylation
chemical_list: D006657:Histones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta
keywords: EZH2; GSK3β; H3K27me3; cancer; phosphorylation