過去對於基因調控的研究發現，組蛋白甲基化/去甲基化 (histone methylation/demethylation) 會導致染色質絲的結構發生改變，屬於一種基因鹼基序列以外的遺傳性變化。此種轉譯後修飾 (post-translational modifications) 在調控基因的表現上扮演了很重要的角色。然而近年來發現，異常的轉錄後修飾會影響生物的生理運作，並導致細胞癌化。KDM8是一種具有JmjC domain的組蛋白去甲基酶，可以針對組蛋白H3尾端接了兩個甲基的第36個lysine residue (H3K36me2) 進行去除甲基的反應，並且被發現可調控胚胎發育、破骨細胞生成，以及細胞增生。由於近期發現KDM8在乳癌細胞中具有高度的表現，並可促進癌細胞的生長，因此異常的KDM8表現目前被認為是導致乳癌發生的可能原因之一。腫瘤發育的過程中，迅速增殖的癌細胞會使周圍形成一種缺氧的環境，並且引發低氧誘導因子1α (HIF-1α) 的表現。由我們先前的實驗發現， KDM8的表現量會因缺氧的刺激而上升，並且可和HIF-1α結合。此外，抑制KDM8可阻止乳癌細胞的轉移。因此本研究之主要目的在於探討KDM8對於缺氧環境引發的乳癌細胞增生及癌細胞轉移機制的調控。實驗結果發現乳癌細胞的增情形生不僅因KDM8的表現受抑制而減緩，且在KDM8的缺乏在缺氧環境下對抑制乳癌細胞生長具有明顯的效果。經由進一步的實驗證實，抑制KDM8會導致周期素 (cyclin)、細胞週期蛋白依賴型激酶 (cyclin-dependent kinase, CDK) 以及細胞週期抑制蛋白 (p21, p27) 等許多細胞週期調控因子的表現量發生改變，進而將細胞滯留在細胞週期的G1及G2週期。本研究也發現缺氧所引發的c-Myc及p53活性增加現象會因KDM8的表現量下降而被抑制，並且許多促進癌細胞轉移因子的表現量也因KDM8受到抑制而下降。上述受到調控的基因中，有許多過去都曾被證明為Wnt 訊號通路(Wnt signaling)的下游調控基因。因此，由上述結果推測，KDM8可能藉由調控Wnt的訊號傳遞路徑，進而影響乳癌細胞之增生及轉移機制。

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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