2015-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/702256摘要：癌症的起源與進程是由基因與後基因層次所控制。越來越多的證據顯示，後基因的基因靜默化經常是造成癌症的腫瘤抑制基因的缺損。最有名的後基因標記是DNA 甲基化，受組蛋白結構修飾的影響，在癌症生物學中組蛋白結構受到改變並且伴演調節的角色。G9a 為一個含有SET domain 的蛋白，是一種哺乳動物的組蛋白甲基轉移酶負責催化組蛋白H3K9 的甲基化。越來越多研究證實，G9a 有助於腫瘤抑制基因的非遺傳層次沉默與和保持細胞惡性特徵。在過去的幾年中，我們完成了一些人類子宮內膜癌及卵巢癌組織的調查研究，在體外試驗研究，致力於說明G9a 在婦科癌症中扮演致病的角色。我們證實了較高的G9a 與卵巢癌及子宮內膜癌侵襲及較差的預後有關。此外，我們在G9a 的生物功能研究中發現，它可以改變癌症發展中多種細胞的功能，包括黏附、遷移、侵襲、失巢凋亡、自體吞噬及癌症幹細胞的維持。DNMT 抑制劑和HDAC 抑制劑已經被證實出具有抗腫瘤的效果，目前還在臨床試驗測試。隨著許多針對參與表現的非遺傳層次調控之特定酵素的藥物出現，利用非遺傳層次標靶是有效跟有價值的方式如同癌症的化學治療及化學預防治療。我們早期的研究顯示G9a 在癌症的發展上不僅是一個重要的角色，也可能提供一個新藥物開發的目標。基於我們已經了解G9a 在婦科癌症的致病作用，我們提出了一個多年計畫，以擴大對G9a 使腫瘤侵襲與轉移的知識。隨著癌症的形成更深入的了解G9a 的作用，我們將有潛力解開用標靶G9a 治療婦科癌症非遺傳層次癌症。<br> Abstract: The initiation and progression of cancer is controlled by both genetic and epigeneticevents. Increasing evidence indicates that epigenetic gene silencing frequently provide forloss of tumor suppressor genes in cancer. The best-known epigenetic marker is DNAmethylation which influenced by the modifications in histone structure that are commonlydisrupted in cancer cells and serve a key regulatory role in cancer biology. G9a, a SETdomain-containing protein, is a novel lysine-preferring mammalian histone methyltransferasethat responsible for the majority of euchromatic histone H3 lysine 9 methylation. Growingevidence suggests that G9a contributes to the epigenetic silencing of tumor suppressor genesand maintain the malignant phenotype. Over the past few years, we have completed severalinvestigative studies on human endometrial and ovarian cancer tissues, in vitro experimentalstudies, aiming to elucidate the pathogenic role of G9a in human gynecologic cancers. Ourwork has demonstrated that G9a level is highly correlated with aggressiveness and poorprognosis of ovarian and endometrial cancer patients. Moreover, our studies on the biologicalfunctions of G9a revealed that it alters multiple cellular functions critically involved in tumorprogression, including adhesion, migration, invasion, anoikis, autophagy, and cancer stem cellmaintenance.A number of DNMT inhibitors and HDAC inhibitors have been shown to have antitumoreffects and are being tested in clinical trials. With the advent of numerous drugs that targetspecific enzymes involved in the epigenetic regulation of gene expression, the utilization ofepigenetic targets is emerging as an effective and valuable approach to chemotherapy as wellas chemoprevention of cancer. The results of our earlier studies have not only shed light on anessential role of G9a in cancer progression, but also provided a possible new target for drugdevelopment. Based on what we have understood the pathogenic role of G9a in gynecologiccancers, we proposed this multi-year research project to fully extend current knowledge ofG9a in driving tumor invasion and metastasis. With the in-depth understanding of G9a incarcinogenesis, we will be able to unlock the potential of epigenetic cancer therapy forgynecologic cancers by targeting G9a.