GSK3β inactivation promotes the oncogenic functions of EZH2 and enhances methylation of H3K27 in human breast cancers.
GSK3β inactivation promotes the oncogenic functions of EZH2 and enhances methylation of H3K27 in human breast cancers.
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DOI：
10.18632/oncotarget.11008
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发表时间：
2016-08-30
期刊：
影响因子：
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通讯作者：
Hung MC
中科院分区：
文献类型：
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作者：
Ko HW;Lee HH;Huo L;Xia W;Yang CC;Hsu JL;Li LY;Lai CC;Chan LC;Cheng CC;Labaff AM;Liao HW;Lim SO;Li CW;Wei Y;Nie L;Yamaguchi H;Hung MC
在肿瘤发生过程中，肿瘤抑制因子的失活是一个关键步骤。EZH 2是一种组蛋白甲基转移酶，通过催化组蛋白H3在Lys 27位的三甲基化（H3 K27 me 3）促进细胞生长和迁移，在肿瘤发生中起重要作用。它的表达可以通过磷酸化来控制。然而，肿瘤抑制激酶对EZH 2活性的调节还不清楚。在这项研究中，我们发现糖原合成酶激酶3 β（GSK 3 β）负调控H3 K27三甲基化。我们还验证了GSKβ与EZH 2的物理相互作用，并且它们的相互作用发生在胞质溶胶中。在体外，GSK 3 β使EZH 2的Ser 363和Thr 367磷酸化，在体内，激活GSK 3 β上调Thr 367磷酸化。表达GSK 3 β-non-phosphorylatable突变体EZH 2的细胞具有更高的H3 K27三甲基化和增强的细胞迁移和锚定非依赖性生长能力。在乳腺癌患者的肿瘤组织中，通过其Ser 9磷酸化测量的GSK 3 β的失活与较高水平的H3 K27三甲基化正相关。我们的研究表明，GSK 3 β磷酸化EZH 2的Ser 363和Thr 367，导致减少H3 K27三甲基化和EZH 2在乳腺癌中的生物活性。
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.