| Summary: | 碩士 === 國立清華大學 === 分子與細胞生物研究所 === 101 === Methylation/demethylation of histone tail, one of the major post-translational modifications (PTMs) in chromatin, plays an important role in chromatin remodeling to regulate gene expression. Dysregulation of these processes links to carcinogenesis. KDM8 (Jmjd5), an H3K36me2 histone demethylase containing jmjC domain, is crucial to regulate embryonic development, osteoclastogenesis and cell proliferation. Along with its general over expression in breast cancer, KDM8 is suggested to play a role in carcinogenesis. Swiftly proliferating cancer cells that encounter intermittent hypoxia trigger the expression of a master regulator, Hypoxia-inducible factor (HIF). We have previously found that KDM8 interacted with HIF1-α and was up-regulated under hypoxia (by Dr. Hung-Jung Wang). Moreover, knockdown KDM8 inhibited breast cancer cell metastasis (by So-Fang Yang). In this study, we aim to address the mechanism in which KDM8 is involved in cell proliferation under hypoxia, as well as tumor metastasis. A significantly reduced level of cell proliferation was found in KDM8 knockdown cells, especially when these cells were cultured under hypoxia. Knockdown cells were arrested in both G1/S and G2/M phases. Several cell cycle transition regulatory proteins including cyclins, cyclin-dependent kinases (CDKs), and cyclin-CDK complex inhibitors were affected accordingly. Moreover, KDM8 knockdown cells significantly lost hypoxia-induced c-Myc and p53 transactivation activity. And several epithelial mesenchymal transition inducers which belong to downstream targets of canonical Wnt signaling exhibited a lower level of expression, suggesting a link to hypoxia-induced Wnt signaling pathway.
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