順鉑(Cisplatin)廣泛被用於治療卵巢癌、肺癌、乳癌等癌症。但長時間施打順鉑藥物，常造成癌細胞產生抗藥性，增加治療難度。先前研究證實，鼻咽癌細胞抗藥性生成與DNA修復路徑相關。我們認為鼻咽癌細胞在長期順鉑處理下，發生染色質重塑(Chromatin remodeling)現象，強化DNA修復路徑提高抗藥性，而組蛋白乙醯轉移酶會參與染色質重塑。MORF基因屬於MYST家族，其蛋白具組蛋白乙醯轉移酶(Histone acetyltransferase，HAT)功能，與MOZ、BRPF1/2/3、ING5及hEAf6形成複合體，乙醯化組蛋白H3K9、H3K14或H3K23等位點，或與轉錄因子共同調控基因表現。先前實驗發現降低順鉑抗藥性鼻咽癌細胞內MORF基因表現量，會提高對順鉑藥物敏感性，范可尼貧血(Fanconi Anemia，FA)及同源重組(Homologous recombination，HR)等修復路徑相關基因表現減少。本篇研究以MORF基因抑制及MORF基因缺失鼻咽癌細胞株證實，缺少MORF基因使鼻咽癌細胞提高對順鉑敏感性，且減少姊妹染色體交換(Sister chromatid exchange，SCE)與減少范可尼貧血及同源重組路徑基因及蛋白表現，而與核苷酸切除修復(Nucleotide excision repair，NER)或模板置換(Template switching，TS)路徑較無關聯。我們用染色質免疫沉澱實驗(Chromatin Immunoprecipitation，ChIP)證明MORF有類似轉錄因子的功能，結合在FANCD2和BRCA1基因啟動子上，調控范可尼貧血與同源重組修復路徑下游表現。除此之外，發現到MORF會協助啟動停滯的DNA複製叉(DNA stalled fork)。總結以上結果，我們認為MORF能與FANCD2、BRCA1基因啟動子結合，調控細胞范可尼貧血與同源重組修復路徑，提高癌細胞抗藥性。為未來鼻咽癌治療提供一個新方向。

Cisplatin is a platinum based chemotherapeutic drug used to treat solid tumors. However, chronic treatment of cancer cells with cisplatin will induce cisplatin resistant phenotype, which is the major obstacle for the efficacy of the treatment. Previous studies have shown that DNA repair pathways, including Fanconi anemia, homologous recombination, and postreplication repair, contribute to the drug resistant phenotype of nasopharyngeal cancer cells (NPC). We hypothesize that the cisplatin resistant NPC cells undergo chromatin remodeling to enhance DNA repair pathways to repair cisplatin caused DNA lesions. MORF belongs to the MYST family of histone acetyltransferase (HAT). MORF forms a complex with its homolog MOZ, which is able to acetylate histones H3. Additionally, the MORF/MOZ complex can interact with some transcription factors, such as TP53, to regulate gene expression. Here we demonstrate that the MORF deficient HONE6 cells show increased sensitivity to cisplatin, reduced numbers of sister chromatid exchange (SCE), and down-regulation of Fanconi anemia (FA) and homologous recombination (HR) pathways. Consistent with these results, MORF is able to bind to the promoters of FANCD2 and BRCA1 by using the chromatin immunoprecipitation (ChIP) assay. Furthermore, MORF is also involved in the restart of DNA replication. In summary, our results suggest that MORF can regulate FA and HR pathways by increasing the expression of FANCD2 and BRCA1, thereby causing the cisplatin-resistant phenotype.

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