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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 康照洲(Jaw-Jou Kang) | |
| dc.contributor.author | Che-Jui Liang | en |
| dc.contributor.author | 梁哲睿 | zh_TW |
| dc.date.accessioned | 2021-06-16T09:46:37Z | - |
| dc.date.available | 2027-01-26 | |
| dc.date.copyright | 2017-03-01 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-01-23 | |
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Genetic vaccines and therapy 5, 10, doi:10.1186/1479-0556-5-10 (2007). 138 Yamaguchi, M. et al. Histone deacetylase 1 regulates retinal neurogenesis in zebrafish by suppressing Wnt and Notch signaling pathways. Development (Cambridge, England) 132, 3027-3043, doi:10.1242/dev.01881 (2005). 139 Klisovic, D. D. et al. Depsipeptide (FR901228) inhibits proliferation and induces apoptosis in primary and metastatic human uveal melanoma cell lines. Investigative ophthalmology & visual science 44, 2390-2398 (2003). 140 Holmes, W. F. et al. Coordinate control and selective expression of the full complement of replication-dependent histone H4 genes in normal and cancer cells. The Journal of biological chemistry 280, 37400-37407, doi:10.1074/jbc.M506995200 (2005). | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/59946 | - |
| dc.description.abstract | 多環芳香烴受體 (aryl hydrocarbon receptor, AhR) 屬 basic-helix-loop-helix (bHLH)/PAS 家族，此家族參與許多生理反應，像是生理週期、代謝及缺氧狀態下的壓力反應。AhR 可以調解許多藥理及毒理效應，包含誘導藥物代謝酵素 CYP1A1、免疫抑制、腫瘤促進。AhR 主要分布於細胞質並與 molecular chaperone complex (Hsp90/XAP2/p23) 結合，當受到外來物質，如：PAHs 的刺激，AhR 活化後會進入細胞核內與芳香烴核轉位蛋白 (aryl hydrocarbon nuclear translocator, ARNT) 形成複合體，此複合體會結合在 XRE/DRE 片段上，進行下游基因的轉錄。附基因體機制包括 DNA 甲基化 (DNA Methylation)、組蛋白之間轉譯後修飾的改變 (post-translational modification of histone proteins) 以及微小 RNA 的表現 (microRNA expression)。組蛋白的轉譯後修飾是附基因體調控中很重要的調控機制之一，常見的轉譯後修飾有乙醯化 (acetlaytion)、甲基化 (methylation)。這些修飾會影響組蛋白間緊密程度，進而影響基因表現。組蛋白間的乙醯化會受到兩種互相結抗的酵素所調控，分別為組蛋白乙醯基轉移酶 (histone acetyltransferase, HATs) 及組蛋白去乙醯基酶 (histone deacetylases, HDACs)。近年來研究發現癌症的發生與進展也和附基因體的失常有關，已有文獻報導 HDAC 過度表現會抑制腫瘤抑制基因 p53 的表現，亦會引起缺氧誘導因子-1 的活化進而誘發血管新生。另一方面，文獻也指出 HDAC 抑制劑，LBH589 可以抑制癌細胞的血管新生作用，過去我們也發現 AhR 與血管新生有關。所以本研究的目的為探討附基因體藥物如何影響 HDAC 並探討 AhR 蛋白與 HDAC 之間如何互相調控。本研究利用胃癌細胞株 AGS 處理 HDAC 抑制劑 (LBH589)，再利用西方點墨法分析組蛋白上的乙醯化程度，結果顯示抑制 HDAC 的活性會增加乙醯化 H4 與 H2BK5 蛋白表現，然後也看到 AhR 靜默的細胞株，乙醯化 H4 與 H2BK5 蛋白表現也明顯降低。細胞氧化壓力實驗發現，處理 LBH589 會造成細胞內氧化壓力產生。此外我們也發現 LBH589 處理不同時間及不同劑量後，AhR 及 Nrf2蛋白表現也隨之增加，具有劑量效應；且也發現隨著處理時間增加，AhR 蛋白具有時間效應，而 Nrf2 蛋白則是 3小時達到最多之後開始減少。參考先前文獻研究結果得知 HDACi 會產生氧化壓力殺死癌細胞，本實驗利用 ROS 抑制劑 NAC 發現 LBH589 所生成的 ROS 跟 AhR 及 Nrf2 蛋白的產生有關，加上使用 Nrf2 抑制劑 brusatol，證明 Nrf2 在 AhR 蛋白生成扮演重要角色。ChIP assay實驗結果發現，LBH589 會使 Nrf2 蛋白與 AhR promoter 結合。進一步利用核質分離實驗發現，LBH589 處理 24小時後會使 AhR 進核，且以 AhR 靜默組也具相同結果。HAT Activity Colorimetric Assay 及 HDAC-Glo I/II Assay 兩個活性實驗發現，A549 細胞之 AhR 靜默與控制組相比，HAT 活性沒有顯著差異；而 HDAC 活性則有明顯增加的趨勢。利用免疫沉澱法分析 AhR 與這些蛋白之間的交互作用，結果得知處理 LBH589 後，AhR 與 HDAC1、HDAC2 及 HDAC3 之間結合增加。免疫螢光染色法進一步證明 AhR 與 HDAC1、HDAC2 及 HDAC3 蛋白之間有進行交互作用。綜合以上結果，本研究發現 LBH589 會使細胞內產生 ROS 並造成 Nrf2 蛋白增加及進入細胞核與 AhR 的啟動子結合，造成 AhR 蛋白表現增加，此內生性機制之 AhR 表現會影響附基因體的調控並導致 HDAC 之負回饋抑制。 | zh_TW |
| dc.description.abstract | Aryl hydrocarbon receptor (AhR) is a ligand-activated protein, it can regulate many effects of pharmacology and toxicology. Recently, the novel function of AhR have been mentioned briefly. Current studies have revealed that changes in epigenetic regulation can alter AhR protein expression and contribute to healthy problem. Histone acetylation is one of the epigenetic modifications. This modification influence chromatin structure involved gene transcription. There are two enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs), can regulate histone acetylation in this modification. However, the regulation mechanism between AhR and HDAC are not clear. In this study, we investigate the regulation between AhR and HDAC. We used gastric cancer cell lines (AGS) that treated HDACi (LBH589), assayed by Western blot to analyze acetylation of histone. Inhibition of HDACs activity can increase acetylation of histone H4 and H2BK5. Moreover, comparing between the normal AhR cells and the AhR gene knock down cells, we found that the higher acetylation of histone with higher AhR expression level. Cellular reactive oxygen species detection assay showed that LBH589 might produce ROS. Additionally, the result demonstrated that AhR and Nrf2 protein expression was up-regulation with LBH589 treatment in dose-dependent manner. Another result showed that AhR protein expression was up-regulation with LBH589 treatment in time course manner, but Nrf2 protein expression is largest in 3hours. Previous study revealed that HDACi may induce ROS to kill the cancer cell, therefore, we used ROS inhibitor, NAC, and found that increased AhR and Nrf2 protein was related to ROS with LBH589 treatment. Moreover, we utilized Nrf2 inhibitor brusatol to prove that Nrf2 is an important role in AhR production. ChIP assay proved that Nrf2 may bind with AhR promoter sequence with LBH589 treatment. Both of the HDAC-Glo I/II Assay and HAT Activity Colorimetric Assay discovered that activity of HDACs were up-regulation in shAhR A549 cells, but activity of HATs was not. Immunoprecipitation (IP) confirmed that LBH589 treatment increased AhR/HDAC1/HDAC2/HDAC3 complex. Finally, we applied the immunofluorescence staining (IF) to prove AhR can interact with HDAC1, HDAC2, and HDAC3. According to above results, we have acquired conclusion that LBH589 may induce ROS and cause Nrf2 protein bind with AhR promoter. Up-regulation of AhR may regulate epigenetic mechanism and inhibit HDACs activity. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T09:46:37Z (GMT). No. of bitstreams: 1 ntu-106-R03447007-1.pdf: 2817967 bytes, checksum: 93fc3f16f1f0c9548bcd28787d58c41c (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | 目錄 (contents)
口試委員會審定書..................................i 致謝......................................................ii 中文摘要.................................................iii Abstract..................................................v 縮寫表..................................................vii 圖表目錄 (Figures and Tables)...........................xi 第一章、緒論 (Introduction)..............................1 1.1. 多環芳香烴受體 (Aryl hydrocarbon receptor).......1 1.2. 表關遺傳與AhR 調控途徑的關係 (The relationship between the epigenetic and AhR regulator pathway).......3 1.3. 組蛋白乙醯化及去乙醯化 (Histone acetylation and deacetylation)..........................................4 1.4. 組蛋白乙醯化及去乙醯化過程之相關酵素與複合體 (Histone acetylation- and deacetylation-related enzymes and complexes)..............................................6 1.4.1. 組蛋白乙醯基轉移酶 (Histone acetyltransferases, HATs)...................................................6 1.4.2. 組蛋白去乙醯酶 (Histone deacetylases, HDACs).....6 1.4.3. HDAC與HAT複合體 (HDAC and HAT complexes).........8 1.4.4. 組蛋白去乙醯酶抑制劑 (Histone deacetylase inhibitor, HDACi).......................................9 1.5. HDACi 對產生自由基及人體清除氧化壓力系統之關係 (The relationship between HDACi and production of free radicals as well as Nrf2-Keap1 system).................11 1.6. 研究動機........................................12 第二章、材料與方法 (Materials and Methods)...............13 2.1. 實驗材料........................................13 2.1.1. 細胞株 (Cell lines)............................13 2.1.2. 藥品與試劑 (Chemicals and Reagents).............13 2.1.2.1. 細胞培養................................13 2.1.2.2. 西方點墨法..............................13 2.1.2.3. 組蛋白去乙醯酶活性測定 (HDAC activity assay).................................................14 2.1.2.4. 組蛋白乙醯基轉移酶活性測定 (HAT activity assay).................................................14 2.1.2.5. 核質分離 (Nuclear extraction)...........14 2.1.2.6. 染色體免疫沉澱法 (Chromatin Immunoprecipitation, ChIP).............................15 2.1.2.7. 細胞氧化壓力偵測法 (Cellular reactive oxygen species detection assay)........................15 2.1.2.8. 免疫沉澱法 (Immunoprecipitation)........15 2.1.2.9. 其他...................................15 2.1.3. 抗體 (Antibodies)..............................15 2.1.4. 質體 (Plasmid).................................16 2.2. 方法...........................................16 2.2.1. 細胞培養 (Cell culture).........................16 2.2.2. 細胞存活率試驗 (Cell viability assay)...........17 2.2.3. 質體萃取（Plasmid DNA purification）............17 2.2.4. 慢病毒製備與感染 (Lentivirus production and infection).............................................17 2.2.5. 細胞總蛋白質液收集 (Cell lysate collection)......18 2.2.6. 西方墨點法 (Western blotting analysis)..........18 2.2.7. 免疫沉澱法 (Immunoprecipitation)................19 2.2.8. 細胞核質分離 (Nuclear and cytoplasmic fraction).19 2.2.9. 細胞免疫螢光染色法 (Immunofluorescence analysis).20 2.2.10. 組蛋白乙醯基轉移酶活性測定 (HAT activity assay)...20 2.2.11. 組蛋白去乙醯酶活性測定 (HDAC activity assay).....21 2.2.12. 染色體免疫沉澱法 (Chromatin Immunoprecipitation, ChIP)..................................................21 2.2.13. 細胞氧化壓力偵測法 (Cellular reactive oxygen species detection).....................................21 2.2.14. 細胞RNA 萃取 (RNA extraction)...................21 2.2.15. 反轉錄聚合酶鏈鎖反應 (Reverse transcription polymerase chain reaction, RT-PCR).....................22 2.3. 統計分析........................................23 第三章、結果 (Results)..................................24 3.1. 組蛋白去乙醯酶抑制作用對於胃癌細胞株之細胞存活率與細胞型態之影響..............................................24 3.2. 組蛋白去乙醯酶抑制作用會使 AGS 細胞內產生氧化壓力...24 3.3. 組蛋白去乙醯酶抑制作用誘導 AhR 及 Nrf2 蛋白表現增加.....................................................25 3.4. 組蛋白去乙醯酶抑制作用所產生的氧化壓力會誘使 Nrf2 及 AhR 蛋白表現增加........................................25 3.5. 組蛋白去乙醯酶抑制作用誘使 Nrf2 增加不是透過轉錄生成.....................................................26 3.6. Nrf2 與 AhR 基因轉錄之關係.......................26 3.7. Nrf2 會與 AhR 啟動子結合........................27 3.8. AhR 參與組蛋白乙醯化過程.........................27 3.9. 組蛋白去乙醯酶抑制作用誘導 AhR 進入細胞核內........28 3.10. AhR 對組蛋白乙醯轉移酶 (Histone acetyltransferases, HATs) 及組蛋白去乙醯酶 (Histone deacetylases, HDACs) 活性之影響...................................................28 3.11. AhR 與 HDAC 和 CBP 的交互作用...................29 3.12. 免疫螢光染色證明 AhR 與 HDAC 的交互作用...........30 第四章、討論 (Discussion)...............................31 4.1 ROS 的產生與AhR 生合成之關係.....................31 4.2 LBH589 對於胃癌與肺癌的治療......................33 4.3 組蛋白乙醯化與癌症之關係..........................35 4.4 LBH589 讓總組蛋白 4 蛋白表現增加.................36 第五章、結論 (Conclusion)...............................37 參考文獻 (References)...................................38 圖表 (Figures and Tables)..............................51 圖表目錄 (Figures and Tables) Figure I. AhR signaling pathway……………………………………………….…....1 Figure II. Histone acetylation is generally linked to transcriptional activation......5 Figure III. Multiple HDAC inhibitors (HDACi)-activated antitumor pathways...10 Figure IV. Structure of panobinostat………………………………………….……10 Figure 1. The cell viability and cell morphology in AGS gastric cancer cell lines with LBH589 treatment………………………...……………………………………51 Figure 2. HDACi, LBH589, can induce intracellular ROS……….……………….53 Figure 3. The expression of AhR and Nrf2 protein in dose-dependent and time course manner…………………………………………………….………………….54 Figure 4. HDACi, LBH589, can induce intracellular ROS and increase the expression of AhR protein………………………………………………..………….56 Figure 5. The mRNA expression of Nrf2 increased is due to degradation cessation………………………………………………………………………………58 Figure 6. Nrf2 can induce the expression of AhR protein With LBH589 treatment……………………………………………………………………...………59 Figure 7. Nrf2 may bind to AhR promoter in human AGS gastric cancer cell lines with LBH589 treatment……………………………………………..…………….…61 Figure 8. HDACi, LBH589, induced histone acetylation in gastric cancer cell lines…………………………………………………………………………...……….62 Figure 9. The expression of AhR proteins in A549 and shAhR cells with LBH589 treatment in cytoplasma and nucleus……………………………………...………..63 Figure 10. The pan-HDAC activity and pan-HAT activity in A549 and shAhR A549 cells……………………………………………………………..………………64 Figure 11. AhR may interact with HDACs in A549 normal and shAhR cell with LBH589 treatment………………………………………………………..………….65 Figure 12. AhR may increase interaction with HDAC protein with LBH589 treatment……………………………………………………………………….……..67 Figure 13. Schema of pathway by which HDACi induces AhR expression that plays a role in histone acetylation………………………………………..…….……68 Table 1. Primer sequences used for RT-PCR…………………………...…………..69 Table 2. AhR promoter primer for ChIP assay……………………..…...…………70 | |
| dc.language.iso | zh-TW | |
| dc.subject | 氧化壓力 | zh_TW |
| dc.subject | 組蛋白去乙醯?抑制劑 | zh_TW |
| dc.subject | 多環芳香烴受體 | zh_TW |
| dc.subject | 組蛋白乙醯化 | zh_TW |
| dc.subject | NF-E2 相關因子 2 | zh_TW |
| dc.subject | 組蛋白去乙醯? | zh_TW |
| dc.subject | HDAC | en |
| dc.subject | Histone acetylation | en |
| dc.subject | Nrf2 | en |
| dc.subject | HDACi | en |
| dc.subject | AhR | en |
| dc.subject | ROS | en |
| dc.title | 多環芳香烴受體對組蛋白乙醯化修飾之探討 | zh_TW |
| dc.title | The Role of Aryl Hydrocarbon Receptor in Acetylation Modification of Histone | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 譚賢明(Bertrand Tan),李珍珍(Chen-Chen Lee) | |
| dc.subject.keyword | 多環芳香烴受體,組蛋白去乙醯?抑制劑,NF-E2 相關因子 2,組蛋白乙醯化,氧化壓力,組蛋白去乙醯?, | zh_TW |
| dc.subject.keyword | AhR,HDACi,Nrf2,Histone acetylation,ROS,HDAC, | en |
| dc.relation.page | 70 | |
| dc.identifier.doi | 10.6342/NTU201700155 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-01-24 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| 顯示於系所單位： | 毒理學研究所 | |
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