Oncotarget

Research Papers:

GSK3β inactivation promotes the oncogenic functions of EZH2 and enhances methylation of H3K27 in human breast cancers

How-Wen Ko, Heng-Huan Lee, Longfei Huo, Weiya Xia, Cheng-Chieh Yang, Jennifer L. Hsu, Long-Yuan Li, Chien-Chen Lai, Li-Chuan Chan, Chien-Chia Cheng, Adam M. Labaff, Hsin-Wei Liao, Seung-Oe Lim, Chia-Wei Li, Yongkun Wei, Lei Nie, Hirohito Yamaguchi and Mien-Chie Hung _

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Oncotarget. 2016; 7:57131-57144. https://doi.org/10.18632/oncotarget.11008

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Abstract

How-Wen Ko1,2,3, Heng-Huan Lee1,2, Longfei Huo1, Weiya Xia1, Cheng-Chieh Yang1,2,4, Jennifer L. Hsu1,5,8, Long-Yuan Li5,6, Chien-Chen Lai7, Li-Chuan Chan1,2, Chien-Chia Cheng1, Adam M. Labaff1,2, Hsin-Wei Liao1,2, Seung-Oe Lim1, Chia-Wei Li1, Yongkun Wei1, Lei Nie1, Hirohito Yamaguchi1, Mien-Chie Hung1,2,5,8

1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

2The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA

3Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 333, Taiwan

4Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei 112, Taiwan

5Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan

6Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan

7Institute of Molecular Biology, National Chung Hsing University, Taichung 402, Taiwan

8Department of Biotechnology, Asia University, Taichung 413, Taiwan

Correspondence to:

Mien-Chie Hung, email: mhung@mdanderson.org

Keywords: EZH2, GSK3β, H3K27me3, cancer, phosphorylation

Received: April 19, 2016    Accepted: July 19, 2016    Published: August 2, 2016

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.


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