2013-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/648349摘要：基因外修飾在人類癌症中被發現對腫瘤的啟動、促進、侵襲、轉移和化學療法藥物的抗藥性有貢獻。基因外調控方式包括去氧核糖核酸甲基化、組織蛋白修飾和微核糖核酸對轉譯後的基因調控。MYST4 (亦稱MORF)是組織蛋白乙酰基移轉酶，在人的數種腫瘤中被發現有基因易位，包括血液腫瘤和子宮肌瘤以及像Noonan 症候群的病人中。在卵巢癌細胞株中對包含PHD-domain 基因的SAGE(基因表現的連續分析)研究中，MYST4被發現有高度表現。我們在卵巢癌的初步研究顯示MYST4 的高度表現主要發生於高惡性度漿液癌，其在高惡性度漿液癌的表現和更差的整體存活率有相關。此結果顯示MYST4 的表現在卵巢癌中會使腫瘤有更加侵略的行為。為了要闡明MYST4 在卵巢癌中表現的機轉和調控，我們首先計劃研究MYST4 在復發性卵巢癌的表現，推測MYST4 的表現也許與腫瘤的復發和因而具較侵略性的行為有關。其次，我們計劃在卵巢癌細胞株中建立體外MYST4 的高度表現和擊倒系統來探討MYST4 在細胞生長、遷移、侵襲和抗藥性的角色。最後我們嘗試藉由微矩陣和ChIP-CHIP 來尋找受MYST4 調控的路徑，以及MYST4 和基因作用的位置。此研究結果預計可以揭露MYST4 在卵巢癌如何導致腫瘤的侵襲性以及發現生物標誌以做為預後的預測和治療標的。<br> Abstract: Epigenetic modification has been found to contribute to neoplastic initiation, promotion,invasion, metastasis and chemoresistance in human cancers. Epigenetic regulation includesDNA methylation, histone modifications and posttranscriptional gene regulation bymicroRNAs. MYST4 (also known as MORF) is a histone acetyltransferase. Translocation ofMYST4 had been found in several types of human tumors, including hematologic neoplasms,uterine leiomyomas and in patients with Noonan-like syndrome. From the SAGE (serialanalysis of gene expression) study of PHD-domain containing genes in ovarian cancer celllines, MYST4 was found to be highly over-expressed. Our preliminary study revealed thatMYST4 is predominantly over-expressed in ovarian high-grade serous carcinoma, and theexpression in advanced tumors correlated with worse overall survival. These data suggest thatMYST4 is associated with a more aggressive behavior in ovarian carcinoma. To elucidate themechanism of MYST4 expression and regulation in ovarian carcinoma, we first plan to studythe expression of MYST4 in recurrent ovarian carcinomas, speculating that MYST4over-expression may be related to tumor recurrence and thus aggressive behavior. Secondly,we plan to establish in vitro systems in ovarian cancer cell lines to study the effect of MYST4over-expression and knockdown, and to investigate the role of MYST4 in cellular growth,migration, invasion, and chemorsistance. Lastly we try to elucidate the pathways regulated byMYST4 by comparing the expression profile before and after MYST4 induction, and byChIP-CHIP to find the biding sites of genes of interest. The study result is expected to revealhow MYST4 leads to worse prognosis in ovarian carcinoma and find biomarkers and targetsfor outcome prediction and treatment.基因外修飾組織蛋白乙酰基移轉酶MYST4卵巢癌epigenetic modificationhistone acetyltransferaseMYST4ovarian carcinoma