期刊
ONCOTARGET
卷 7, 期 35, 页码 57131-57144出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.11008
关键词
EZH2; GSK3 beta; H3K27me3; cancer; phosphorylation
资金
- National Institutes of Health [CA109311, CA099031, CCSG CA016672]
- Patel Memorial Breast Cancer Endowment Fund
- Susan G. Komen Foundation [SAC 110016]
- University of Texas MD Anderson Cancer Center-China Medical University
- Hospital Sister Institution Fund
- Ministry of Science and Technology, International Research-intensive Centers of Excellence in Taiwan (I-RiCE) [MOST 105-2911-I-002-302]
- Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence [MOHW105-TDU-B-212-134003]
- Center for Biological Pathways
- MD Anderson CPRIT Graduate Scholar Training Program
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 (GSK3 beta) negatively regulates H3K27 trimethylation. We also validate that GSK beta physically interacts with EZH2, and their interaction occurs in the cytosol. GSK3 beta phosphorylates EZH2 at Ser363 and Thr367 in vitro, and activating GSK3 beta upregulates Thr367 phosphorylationin vivo. Cells expressing GSK3 beta-non-phosphorylatable mutant EZH2 have higher H3K27 trimethylation and enhanced ability of cell migration and anchorage-independent growth. Inactivation of GSK3 beta 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 GSK3 beta phosphorylates EZH2 at Ser363 and Thr367, resulting in reduced H3K27 trimethylation and biological activity of EZH2 in breast cancer.
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