Date of Graduation
Doctor of Philosophy (PhD)
During the process of tumorigenesis, inactivation of tumor suppressors is a critical step. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and the enzymatic core subunit of polycomb repressive complex 2 (PRC2), 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. Glycogen synthase kinase 3 beta (GSK3b), a multifunctional serine/threonine kinase, is involved in many cellular processes. GSK3b also participates in neoplastic transformation, tumor development and regulate cancer cell metastasis. Inactivation of GSK3b contributes to tumor development in certain types of cancers, such as breast cancer. In this study, we found that GSK3b negatively regulates H3K27 trimethylation. We also validated that GSK3b physically interacts with EZH2 and their interaction mainly exists in the cytosol. GSK3b phosphorylates EZH2 at Ser363 and Thr367 in vitro, and activating GSK3b upregulates Thr367 phosphorylation in vivo. Cells expressing mutant EZH2 to block phosphorylation by GSK3b have higher H3K27 trimethylation and enhanced ability of cell migration and anchorage-independent growth. Inactivation of GSK3b as measured by its phosphorylation at Ser9 is positively correlated with higher level of H3K27 trimethylation in breast cancer patients. Our study indicates that GSK3b has a critical role in regulating EZH2-mediated oncogenesis.
EZH2, GSK3 beta, H3K27me3, Cancer, Phosphorylation