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系統識別號 U0026-1312201211112700
論文名稱(中文) 探討DNA甲基轉移酵素和組蛋白去乙醯化酵素之變異機制及其抑制劑用於肺癌治療應用性
論文名稱(英文) The alterations of DNA methyltransferase and histone deacetylase and their application for lung cancer treatment
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 101
學期 1
出版年 101
研究生(中文) 湯硯安
研究生(英文) Yen-An Tang
學號 s58981010
學位類別 博士
語文別 英文
論文頁數 140頁
口試委員 指導教授-王憶卿
召集委員-賴明德
口試委員-蔡少正
口試委員-呂佩融
口試委員-洪文俊
口試委員-阮麗蓉
中文關鍵字 肺癌  DNA甲基酵素轉移酵素3A  RB  MDM2  組蛋白去乙醯化酵素抑制劑  細胞質分裂  細胞凋亡  腫瘤生長 
英文關鍵字 lung cancer  DNA methyltransferase 3A  RB  MDM2  histone deacetylase inhibitor  cytokinesis  apoptosis  anti-tumor growth 
學科別分類
中文摘要 研究背景:肺癌是目前世界上造成癌症死亡的首要原因;其中非小細胞肺癌的五年存活率甚至低於16%,且其治療策略的效果仍然有限。表觀遺傳變異 (epigenetic alteration) 是癌症形成的重要因素之一。啟動子過度甲基化和組蛋白去乙醯化等表觀遺傳變異會造成抑癌基因之不表達,進而導致肺癌之生成。DNA甲基酵素轉移酶3A (DNA methyltransferase 3A, DNMT3A) 是一個主要負責催化de novo DNA甲基化的酵素,且在許多癌症中都有過度表現的情形,然而導致其過度表現的機制尚未明瞭。此外,組蛋白去乙醯酶 (histone deacetylases, HDACs) 則是負責組蛋白去乙醯化的酵素,在許多癌症種也都有高度表達或活性增加的情形;目前已發現組蛋白去乙醯酶抑制劑 (HDAC inhibitor) 可以透過促使細胞週期停滯、細胞凋亡、或細胞分化等方式達到抑制癌症的功效,然而應用於治療固態腫瘤的組蛋白去乙醯酶抑制劑仍有待發展。

研究結果:本研究發現在肺癌中過度表達DNMT3A與異常MDM2/RB調控有關。透過細胞和臨床模式研究,我們發現在肺癌細胞和病患中,MDM2會促進RB蛋白質降解,因而干擾了RB對於DNMT3A基因轉錄抑制之作用,進而造成DNMT3A過度表達以及抑癌基因啟動子之異常過度甲基化。在動物實驗中,我們發現使用Nutlin-3這個MDM2的小分子抑制劑,可以有效地抑制腫瘤生長並降低活體內DNMT3A蛋白表現量,也顯著地降低抑癌基因啟動子甲基化程度。這些結果顯示RB/E2F 訊息路徑可以部份地抑制DNMT3A基因的轉錄作用,而此抑制作用會被過度表達的MDM2蛋白質所削弱,因此MDM2的抑制劑可應用在反轉異常的表觀遺傳過程而作為抗癌藥物。此外,本研究亦探討一個新穎的組蛋白去乙醯酶抑制劑OSU-HDAC-44在細胞和動物模式中抑制肺癌的功效和相關機制。我們發現OSU-HDAC-44是一個廣效性組蛋白去乙醯酶抑制劑,並且在in vitro 和in vivo中,OSU-HDAC-44抑制細胞和腫瘤生長的能力約為其他兩種組蛋白去乙醯酶抑制劑 SAHA和trichostatin A的3至4倍。此外,OSU-HDAC-44會導致細胞週期之mitosis和cytokinesis缺陷,進而引起粒線體誘發之細胞凋亡。最後利用染色質免疫沉澱晶片分析 (Chromatin- immunoprecipitation-on-chip analysis) 鑑定出在全基因組 (genome-wide) 中一群會受到OSU-HDAC-44所導致染色質高度乙醯化之基因。這些結果顯示OSU-HDAC-44是一個有潛力且可應用在肺癌治療上的組蛋白去乙醯酶抑制劑。

研究結論:本研究結果不僅提出了導致肺癌中DNMT3A過度表達的機制,也同時提供了一個使用DNA甲基轉移酶抑制劑和組蛋白去乙醯酶抑制劑作為治療肺癌藥物的證據。Nutlin-3和OSU-HDAC-44都是有潛力的表觀遺傳藥物 (epi-drugs),其具有使異常表觀遺傳過程回復正常的新穎功能,並且可以做為單一藥物治療或合併用藥治療的抗癌藥物。
英文摘要 Background: Lung cancer is the leading cause of cancer-related deaths worldwide. The 5-year overall survival of non-small cell lung cancer (NSCLC) is less than 16%, partly due to the limited efficacy of therapeutic strategy for NSCLC. The abnormal DNA hypermethylation and histone deacetylation are two important epigenetic mechanisms leading to silencing of tumor suppressor genes (TSGs), which have been well identified to be associated with tumorigenesis of lung cancer. DNA methyltransferase 3A (DNMT3A), a key enzyme for de novo DNA methylation, is overexpressed in many cancers, however, the underlying mechanism leading to its overexpression remains unclear. In addition, the classical histone deacetylases (HDACs), which are key enzymes responsible for histone deacetylation, show elevated expression and/or upregulation in various cancers. HDAC inhibitors have been shown to exhibits potent antitumor activities by inducing cell cycle arrest, differentiation and/or apoptosis in diverse cancer cells, whereas validated HDAC inhibitors for the treatment of solid tumors remain to be developed.

Results: The present study showed a link between overexpression of DNMT3A and deregulation of MDM2/RB control in lung cancer. In cell and clinical studies, we elucidated that the MDM2 targeted RB for degradation, thus interfering with the RB-mediated transcriptional repression of DNMT3A, and resulting in DNMT3A overexpression and abnormal 5’CpG hypermethylation in various TSGs in lung cancer cells and patients. In xenograft studies, treatment with Nutlin-3, an MDM2 antagonist, significantly suppressed tumor growth and reduced DNA methylation level of TSGs through downregulation of DNMT3A expression. These results suggested that DNMT3A was transcriptionally repressed, in part, by RB/E2F pathway and the repression could be attenuated by MDM2 overexpression. MDM2 was a potent target for anticancer therapy to reverse aberrant epigenetic status in cancers. In addition, the antitumor activities and mechanisms of a novel HDAC inhibitor OSU-HDAC-44 were demonstrated in cellular and animal models of lung cancer. We found that OSU-HDAC-44 was a pan-HDAC inhibitor and exhibited 3-4 times more effectiveness in suppressing cell proliferation in vitro and tumor growth in vivo compared to SAHA or trichostatin A. In addition, OSU-HDAC-44 induced mitosis and cytokinesis defect followed by mitochondria-mediated apoptosis in both cell and animal models. Chromatin-immunoprecipitation-on-chip analysis revealed the genome-wide target genes which were induced by OSU-HDAC-44-mediated hyperacetylation of chromatin. These results suggested that OSU-HDAC-44 was an HDAC inhibitor and could be applied as targeted anticancer drug for NSCLC chemotherapy.

Conclusion: The results of current study not only reveal underlying mechanism leading to DNMT3A overexpression, but also provide the rationales for inhibition of both DNMTs and HDACs as therapeutic strategy in lung cancer treatment. Nutlin-3 and OSU-HDAC-44 are the potent “epi-drugs” that have novel capabilities to reverse aberrant epigenetic process and can be used as monotherapy or combination therapy for cancer treatment.
論文目次 CONTENTS
中文摘要 II
Abstract IV
誌謝 VI
Contents VIII
Table contents XI
Figure contents XII
Appendix contents XIV
Abbreviations XV
Introduction 1
1. Lung Cancer
1-1. The epidemiology of lung cancer 1
1-2. Treatments of non-small cell lung cancer 1
2. Epigenetic alterations in cancer
2-1. DNA methylation in cancer 3
2-2. Histone modifications in cancer 4
2-3. Aberrant gene silencing by histone deacetylation and DNA methylation 5
3. Deregulation of DNA methyltransferases 3A (DNMT3A) in cancer
3-1. The structures and functions of DNMTs 6
3-2. The functions of DNMT3A 7
3-3. DNMT3A in tumorigenesis 8
3-4. The regulations of DNMT3A in cancers 9
3-5. DNMT inhibitors 11
4. Histone deacetylases (HDACs) as a target for cancer treatment
4-1. Histone deacetylases (HDACs) 12
4-2. HDACs in cancer 13
4-3. HDAC inhibitors 13
5. Cell cycle control
5-1. The engine of G1/S machinery 15
5-2. The engine of G2/M machinery 15
5-3. The regulation of cytokinesis 16
6. Alteration of retinoblastoma (RB) in cancer
6-1. The functions of RB 17
6-2. RB in tumorigenesis 18
6-3. The regulations of RB 19
7. Apoptosis
7-1. Bcl-2 family (B-cell lymphoma 2 family) 20
7-2. Caspases (cysteine-dependent aspartate-specific proteases) 21
7-3. Pathways of apoptosis 22
Materials and Methods 24
1. Cell culture 24
2. Plasmid, RNAi and transfection 24
3. Dual luciferase assay 24
4. RNA extraction, reverse-transcriptase polymerase chain reaction (RT-PCR),
and quantitative RT-PCR assays 25
5. Western blot analysis 25
6. Immunoprecipitation (IP)–Western blot analysis 25
7. Chromatin immunoprecipitation (ChIP)-PCR assay 26
8. DNA affinity precipitation assay (DAPA) 26
9. Quantitative methylation-specific PCR (qMSP) analysis 27
10. Study population 27
11. Immunohistochemistry (IHC) and fluorescence IHC assays 28
12. Xenograft studies 28
13. Preparation of OSU-HDAC-44 29
14. Molecular docking analysis 30
15. In vitro HDAC activity assay 31
16. Analysis of cell viability 31
17. Cell cycle analysis 32
18. Time-lapse analysis 32
19. Early apoptosis detection/phosphatidylserine (PS) staining 32
20. In vitro caspase activity assay 32
21. Chromatin structure profiling assay: ChIP-on-chip assay 33
22. RhoA activation assay 33
23. Statistical analysis 33
Results 35
Part I study: MDM2 overexpression deregulates the transcriptional control of RB/E2F leading to DNA methyltransferase 3A overexpression in lung cancer
1. RB negatively regulates the expression of DNMT3A gene leading to
decrease of methylation level globally and TSG specifically 35
2. RB binds at DNMT3A promoter region through E2F1 to form a
repressive chromatin structure in vitro and in vivo 37
3. MDM2 attenuates the RB/E2F1-mediated transcriptional repression
of DNMT3A expression in cell studies 38
4. Overexpression of DNMT3A resulted from alteration of MDM2/RB
pathway leads to increased methylation of multiple TSGs in clinical studies 39
5. Nutlin-3 decreases DNMT3A expression and DNA methylation level
of TSGs, and inhibits tumor growth in animals 39
Part II study: A novel histone deacetylase inhibitor exhibits antitumor activity via apoptosis induction, F-actin disruption and gene acetylation in lung cancer
1. OSU-HDAC-44 is a potent pan-HDAC inhibitor with its ability to target numerous HDACs and induce protein acetylation 41
2. OSU-HDAC-44 inhibits cell proliferation and shows synergistic effects
with cisplatin regardless of p53 status 42
3. OSU-HDAC-44 induces cytokinesis inhibition and apoptosis 42
4. OSU-HDAC-44 activates the intrinsic apoptotic pathway 44
5. OSU-HDAC-44 increases gene expression by loosening the chromatin
structure 44
6. OSU-HDAC-44 down-regulates F-actin dynamics via srGAP1 induction 45
7. OSU-HDAC-44 inhibits lung tumor xenograft growth in vivo 45
8. OSU-HDAC-44 induces protein acetylation, apoptosis and cytokinesis
inhibition in vivo 46
Discussion 48
Conclusion 57
References 59
Tables 76
Figures 81
Appendix 106

TABLE CONTENTS
Table 1. The correlation between protein expression of DNMT3A in relation
to RB protein expression in NSCLC patients 77
Table 2. Inductions of histone acetylation in 33 common genes of A549 and
H1299 lung cancer cells by OSU-HDAC-44 78
Table 3. The signal pathways involved of 12 common genes from the
ChIP-on-chip analysis of A549 and H1299 lung cancer cells 80

FIGURE CONTENTS

Figure 1. RB represses the activity of DNMT3A promoter and promoter
containing E2F1-binding site 82
Figure 2. RB downregulates DNMT3A mRNA and protein expression levels
in human cancer cell lines 83
Figure 3. RB reduces promoter methylation of multiple TSGs and global
5’-methylcytosine 84
Figure 4. RB-mediated repression of DNMT3A gene expression leads to
reduction in promoter methylation of multiple TSGs 85
Figure 5. E2F1 positively regulates DNMT3A gene expression and is
required for RB mediated-repression of DNMT3A 86
Figure 6. DAPA assay shows the binding of RB and E2F1 to the DNMT3A
P2 region 87
Figure 7. MDM2 enhances overexpression of DNMT3A 88
Figure 8. Expression of DNMT3A, RB and MDM2 proteins and analysis of methylation status in surgically resected NSCLC tumors 89
Figure 9. Nutlin-3 inhibits A549 xenograft growth and effectively
downregulates DNMT3A and DNA methylation status of
TSGs in tumor xenograft 90
Figure 10. Chemical structure, molecular docking analysis, and the effect of OSU-HDAC-44 on the biomarkers associated with broad inhibition
on numerous HDACs 91
Figure 11. OSU-HDAC-44 increased p21 mRNA and protein levels in a p53-independent manner. 93


Figure 12. OSU-HDAC-44 inhibits cell proliferation and shows synergistic
effects with cisplatin 94
Figure 13. Effects of OSU-HDAC-44 on cell cycle distribution 95
Figure 14. Effects of OSU-HDAC-44 on cell cycle-regulatory proteins 96
Figure 15. OSU-HDAC-44 inhibits cytokinesis and results in bi-nucleated cells 97
Figure 16. OSU-HDAC-44 induces ubiquitination and degradation of
Aurora B and survivin proteins 98
Figure 17. OSU-HDAC-44 induces intrinsic apoptosis pathway 99
Figure 18. OSU-HDAC-44 decreased RhoA activity via srGAP1 induction,
leading to F-actin dysregulation 100
Figure 19. OSU-HDAC-44 effectively induced apoptosis and inhibited A549 xenograft growth 101
Figure 20. The body weight, H&E staining of major organs, and hematological biochemistry examinations of tested animals 102
Figure 21. E2F1 positively regulates DNMT3A protein expression in 5637 and H1299 cancer cells 103
Figure 22. Model for the transcription regulation mediated by MDM2/RB on DNMT3A promoter 104
Figure 23. The antitumor activity of OSU-HDAC-44 via cytokinese defect,
F-actin disruption, apoptosis induction, and gene acetylation 105

APPENDIX CONTENTS
Appendix Table 1. The plasmids and their characteristics used in the current
study 107
Appendix Table 2. List of siRNA sequences and their characteristics used
in the current study 108
Appendix Table 3. The primers and probes used in the current study 109
Appendix Table 4. The antibodies and their reaction conditions used
in the present study 112
Appendix Figure 1. Functional domain of human methyltransferase family
members 115
Appendix Figure 2. Chemical structures of DNMT inhibitors and the modes
of their actions 116
Appendix Figure 3. Classification, structures, and cellular localization of Zn2+
dependent and NAD+ dependent HDAC isoforms 117
Appendix Figure 4. Structures of major classes of HDAC inhibitors 118
Publication 1 MDM2 overexpression deregulates the transcriptional control of RB/E2F leading to DNA methyltransferase 3A overexpression in lung cancer. Clin. Cancer Res., 18:4325-4333, 2012. 119
Publication 2 A novel histone deacetylase inhibitor exhibits antitumor activity via apoptosis induction, F-actin disruption and gene acetylation in lung cancer. PLoS One, 5:e12417, 2010. 128

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