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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李明學(Ming-Shyue Lee) | |
| dc.contributor.author | Hsin-Hao Tsai | en |
| dc.contributor.author | 蔡心浩 | zh_TW |
| dc.date.accessioned | 2021-06-17T01:36:11Z | - |
| dc.date.available | 2027-08-01 | |
| dc.date.copyright | 2017-09-08 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-08-01 | |
| dc.identifier.citation | 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30
2. Welfare 台MoHa. 104年主要死因統計結果分析. 104年(2015) 3. Shen MM, Abate-Shen C. Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev 2010;24:1967-2000 4. Wang Q, Li W, Liu XS, Carroll JS, Janne OA, Keeton EK, et al. A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. Mol Cell 2007;27:380-92 5. Amaral TM, Macedo D, Fernandes I, Costa L. Castration-resistant prostate cancer: mechanisms, targets, and treatment. Prostate Cancer 2012;2012:327253 6. Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest 2010;120:2715-30 7. Strahl BD, Allis CD. The language of covalent histone modifications. Nature 2000;403:41-5 8. Tan M, Luo H, Lee S, Jin F, Yang JS, Montellier E, et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 2011;146:1016-28 9. Albany C, Alva AS, Aparicio AM, Singal R, Yellapragada S, Sonpavde G, et al. Epigenetics in prostate cancer. Prostate Cancer 2011;2011:580318 10. Ellinger J, Kahl P, von der Gathen J, Rogenhofer S, Heukamp LC, Gutgemann I, et al. Global levels of histone modifications predict prostate cancer recurrence. Prostate 2010;70:61-9 11. Greer EL, Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet 2012;13:343-57 12. Huang J, Berger SL. The emerging field of dynamic lysine methylation of non-histone proteins. Curr Opin Genet Dev 2008;18:152-8 13. Morera L, Lubbert M, Jung M. Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. Clin Epigenetics 2016;8:57 14. Espino PS, Drobic B, Dunn KL, Davie JR. Histone modifications as a platform for cancer therapy. J Cell Biochem 2005;94:1088-102 15. Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva FP, Li M, et al. SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat Cell Biol 2004;6:731-40 16. Hamamoto R, Silva FP, Tsuge M, Nishidate T, Katagiri T, Nakamura Y, et al. Enhanced SMYD3 expression is essential for the growth of breast cancer cells. Cancer Sci 2006;97:113-8 17. Kotake Y, Cao R, Viatour P, Sage J, Zhang Y, Xiong Y. pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4alpha tumor suppressor gene. Genes Dev 2007;21:49-54 18. Takawa M, Masuda K, Kunizaki M, Daigo Y, Takagi K, Iwai Y, et al. Validation of the histone methyltransferase EZH2 as a therapeutic target for various types of human cancer and as a prognostic marker. Cancer Sci 2011;102:1298-305 19. Kogure M, Takawa M, Saloura V, Sone K, Piao L, Ueda K, et al. The oncogenic polycomb histone methyltransferase EZH2 methylates lysine 120 on histone H2B and competes ubiquitination. Neoplasia 2013;15:1251-61 20. Lee JM, Lee JS, Kim H, Kim K, Park H, Kim JY, et al. EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex. Mol Cell 2012;48:572-86 21. Kim E, Kim M, Woo DH, Shin Y, Shin J, Chang N, et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 2013;23:839-52 22. Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science 2012;338:1465-9 23. Cho HS, Kelly JD, Hayami S, Toyokawa G, Takawa M, Yoshimatsu M, et al. Enhanced expression of EHMT2 is involved in the proliferation of cancer cells through negative regulation of SIAH1. Neoplasia 2011;13:676-84 24. Lehnertz B, Pabst C, Su L, Miller M, Liu F, Yi L, et al. The methyltransferase G9a regulates HoxA9-dependent transcription in AML. Genes Dev 2014;28:317-27 25. Pless O, Kowenz-Leutz E, Knoblich M, Lausen J, Beyermann M, Walsh MJ, et al. G9a-mediated lysine methylation alters the function of CCAAT/enhancer-binding protein-beta. J Biol Chem 2008;283:26357-63 26. Zhong X, Chen X, Guan X, Zhang H, Ma Y, Zhang S, et al. Overexpression of G9a and MCM7 in oesophageal squamous cell carcinoma is associated with poor prognosis. Histopathology 2015;66:192-200 27. Cho HS, Hayami S, Toyokawa G, Maejima K, Yamane Y, Suzuki T, et al. RB1 methylation by SMYD2 enhances cell cycle progression through an increase of RB1 phosphorylation. Neoplasia 2012;14:476-86 28. Hamamoto R, Toyokawa G, Nakakido M, Ueda K, Nakamura Y. SMYD2-dependent HSP90 methylation promotes cancer cell proliferation by regulating the chaperone complex formation. Cancer Lett 2014;351:126-33 29. Piao L, Kang D, Suzuki T, Masuda A, Dohmae N, Nakamura Y, et al. The histone methyltransferase SMYD2 methylates PARP1 and promotes poly(ADP-ribosyl)ation activity in cancer cells. Neoplasia 2014;16:257-64, 64 e2 30. Huang J, Perez-Burgos L, Placek BJ, Sengupta R, Richter M, Dorsey JA, et al. Repression of p53 activity by Smyd2-mediated methylation. Nature 2006;444:629-32 31. Goodrich DW. The retinoblastoma tumor-suppressor gene, the exception that proves the rule. Oncogene 2006;25:5233-43 32. Abu-Farha M, Lambert JP, Al-Madhoun AS, Elisma F, Skerjanc IS, Figeys D. The tale of two domains: proteomics and genomics analysis of SMYD2, a new histone methyltransferase. Mol Cell Proteomics 2008;7:560-72 33. Brown MA, Sims RJ, 3rd, Gottlieb PD, Tucker PW. Identification and characterization of Smyd2: a split SET/MYND domain-containing histone H3 lysine 36-specific methyltransferase that interacts with the Sin3 histone deacetylase complex. Mol Cancer 2006;5:26 34. Carr SM, Munro S, Kessler B, Oppermann U, La Thangue NB. Interplay between lysine methylation and Cdk phosphorylation in growth control by the retinoblastoma protein. EMBO J 2011;30:317-27 35. Komatsu S, Imoto I, Tsuda H, Kozaki KI, Muramatsu T, Shimada Y, et al. Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma. Carcinogenesis 2009;30:1139-46 36. Zhang X, Tanaka K, Yan J, Li J, Peng D, Jiang Y, et al. Regulation of estrogen receptor alpha by histone methyltransferase SMYD2-mediated protein methylation. Proc Natl Acad Sci U S A 2013;110:17284-9 37. Dong SW, Zhang H, Wang BL, Sun P, Wang YG, Zhang P. Effect of the downregulation of SMYD3 expression by RNAi on RIZ1 expression and proliferation of esophageal squamous cell carcinoma. Oncol Rep 2014;32:1064-70 38. Kunizaki M, Hamamoto R, Silva FP, Yamaguchi K, Nagayasu T, Shibuya M, et al. The lysine 831 of vascular endothelial growth factor receptor 1 is a novel target of methylation by SMYD3. Cancer Res 2007;67:10759-65 39. Mazur PK, Reynoird N, Khatri P, Jansen PW, Wilkinson AW, Liu S, et al. SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature 2014;510:283-7 40. Silva FP, Hamamoto R, Kunizaki M, Tsuge M, Nakamura Y, Furukawa Y. Enhanced methyltransferase activity of SMYD3 by the cleavage of its N-terminal region in human cancer cells. Oncogene 2008;27:2686-92 41. Sponziello M, Durante C, Boichard A, Dima M, Puppin C, Verrienti A, et al. Epigenetic-related gene expression profile in medullary thyroid cancer revealed the overexpression of the histone methyltransferases EZH2 and SMYD3 in aggressive tumours. Mol Cell Endocrinol 2014;392:8-13 42. Vieira FQ, Costa-Pinheiro P, Ramalho-Carvalho J, Pereira A, Menezes FD, Antunes L, et al. Deregulated expression of selected histone methylases and demethylases in prostate carcinoma. Endocr Relat Cancer 2014;21:51-61 43. Wang SZ, Luo XG, Shen J, Zou JN, Lu YH, Xi T. Knockdown of SMYD3 by RNA interference inhibits cervical carcinoma cell growth and invasion in vitro. BMB Rep 2008;41:294-9 44. Zeng B, Li Z, Chen R, Guo N, Zhou J, Zhou Q, et al. Epigenetic regulation of miR-124 by hepatitis C virus core protein promotes migration and invasion of intrahepatic cholangiocarcinoma cells by targeting SMYD3. FEBS Lett 2012;586:3271-8 45. Wu J, Cheung T, Grande C, Ferguson AD, Zhu X, Theriault K, et al. Biochemical characterization of human SET and MYND domain-containing protein 2 methyltransferase. Biochemistry 2011;50:6488-97 46. Leinhart K, Brown M. SET/MYND Lysine Methyltransferases Regulate Gene Transcription and Protein Activity. Genes (Basel) 2011;2:210-8 47. Saddic LA, West LE, Aslanian A, Yates JR, 3rd, Rubin SM, Gozani O, et al. Methylation of the retinoblastoma tumor suppressor by SMYD2. J Biol Chem 2010;285:37733-40 48. Hamamoto R, Saloura V, Nakamura Y. Critical roles of non-histone protein lysine methylation in human tumorigenesis. Nat Rev Cancer 2015;15:110-24 49. Horoszewicz JS, Leong SS, Chu TM, Wajsman ZL, Friedman M, Papsidero L, et al. The LNCaP cell line--a new model for studies on human prostatic carcinoma. Prog Clin Biol Res 1980;37:115-32 50. Igawa T, Lin FF, Lee MS, Karan D, Batra SK, Lin MF. Establishment and characterization of androgen-independent human prostate cancer LNCaP cell model. Prostate 2002;50:222-35 51. Seruga B, Ocana A, Tannock IF. Drug resistance in metastatic castration-resistant prostate cancer. Nat Rev Clin Oncol 2011;8:12-23 52. Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA, Richter M, et al. p53 is regulated by the lysine demethylase LSD1. Nature 2007;449:105-8 53. Abu-Farha M, Lanouette S, Elisma F, Tremblay V, Butson J, Figeys D, et al. Proteomic analyses of the SMYD family interactomes identify HSP90 as a novel target for SMYD2. J Mol Cell Biol 2011;3:301-8 54. Liu C, Wang C, Wang K, Liu L, Shen Q, Yan K, et al. SMYD3 as an oncogenic driver in prostate cancer by stimulation of androgen receptor transcription. J Natl Cancer Inst 2013;105:1719-28 55. Yang YA, Yu J. EZH2, an epigenetic driver of prostate cancer. Protein Cell 2013;4:331-41 56. Yap TA, Smith AD, Ferraldeschi R, Al-Lazikani B, Workman P, de Bono JS. Drug discovery in advanced prostate cancer: translating biology into therapy. Nat Rev Drug Discov 2016;15:699-718 57. Azad AA, Zoubeidi A, Gleave ME, Chi KN. Targeting heat shock proteins in metastatic castration-resistant prostate cancer. Nat Rev Urol 2015;12:26-36 | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/67528 | - |
| dc.description.abstract | 雄激素剝奪治療（ADT）已被廣泛用於前列腺癌（PCa）治療。雖然大多數患者對ADT有良好的早期反應，但是到治療後期，攝護腺癌細胞通常對該療法產生抗性，並且轉變成為具有高轉移潛力的「抗荷爾蒙療法之轉移性攝護腺癌」。 攝護腺癌轉化為抗賀爾蒙療法攝護腺癌（CRPC）的分子機制仍然尚未明瞭。在這項研究中，我分析了表觀遺傳修飾的失調是否在攝護腺癌轉變為抗賀爾蒙療法過程中扮演角色。結果表明，CRPC細胞中甲基轉移酶H的表達水平明顯高於其他組蛋白甲基轉移酶。 甲基轉移酶H剃除顯著降低CRPC細胞的生長和侵襲能力，同時也降低雄激素受體 (AR)和前列腺特異抗體 (PSA)的蛋白表現量。另外，甲基轉移酶H剃除恢復了抗賀爾蒙療法攝護腺癌細胞的雄激素敏感性。 過度表達甲基轉移酶H會促進雄激素依賴性前列腺癌細胞的生長和侵襲能力，並且在雄激素剝奪條件下增加AR和PSA的表達。 除此之外，過表達甲基轉移酶H的 LNCaP細胞生長在雙氫睪酮 (DHT)的刺激下並沒有進一步的提升。這些實驗結果一起證實了甲基轉移酶H會通過促進雄激素受體信號參與攝護腺癌轉變為抗賀爾蒙療法的過程。 | zh_TW |
| dc.description.abstract | Androgen-deprivation therapy (ADT) has been frequently used for prostate cancer (PCa) therapy. Although most patients have a good early response to ADT, however, PCa cells often acquire resistance to this therapy and become “castration resistant” with a high potential of metastasis. The molecular mechanisms how PCa transforms to castration-resistant prostate cancer (CRPC) are still elusive. In this study, I investigated whether dysregulation of epigenetic modifications played a role in the PCa progression to a castration-resistant stage. The results showed that the expression levels of Methyltransferase H (MTH) rather than the other histone methyltransferases were significantly increased in CRPC cells. MTH silencing significantly reduced the growth and invasion abilities of CRPC cells, and decreased the protein levels of AR and PSA. Moreover, MTH knockdown restored the androgen sensitivity of castration-resistant prostate cancer cells. Overexpression of MTH promoted the growth and invasion ability of androgen-dependent prostate cancer cells, and increased the expression of AR and PSA in an androgen-deprivation condition. DHT, a potent androgen, had no further stimulation effect on the growth of MTH-overexpressing LNCaP cells. The results together indicate that MTH is involved in castration-resistant prostate cancer progression via up-regulating AR signaling. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T01:36:11Z (GMT). No. of bitstreams: 1 ntu-106-R04442004-1.pdf: 3719124 bytes, checksum: 1fb971788099100d014a1e24506ada45 (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | 致謝……………………………………………………………………………............I
中文摘要……………………………………………………………………………...II ABSTACT…………………………………………………………………………....III Chapter 1. Introduction 1 1.1 Castration-resistant Prostate cancer 2 1.2 Roles of histone methyltransferases in cancers 3 1.3 The family of histone methyltransferases in cancers 4 1.4 Histone methyltransferase MTH 4 1.5 Research motivation 5 Chapter 2. Materials and Methods 7 Chapter 3. Results 21 3.1 The expression levels of histone methyltransferase MTH was significantly increased in castration-resistant prostate cancer cells. 22 3.2 The expression levels of MTH were increased in castration-resistant C81 LNCaP cells. 23 3.3 Expression levels of histone methyltransferases in C33 and C81 LNCaP cells. 24 3.4 Establishment of castration-resistant prostate cancer cells after anti-androgen treatment. 25 3.5 The expression levels of histone methyltransferases in castration-resistant LNCaP Cas25 and LNCaP C25H cells. 27 3.6 Enhancement of the invasive ability in castration-resistant LNCaP Cas25 and LNCaP C25H cells. 27 3.7 Knockdown of MTH reduces the growth rate and invasion ability of castration-resistant prostate cancer cells. 28 3.8 Overexpression of MTH promotes the growth and invasion abilities of androgen-sensitive prostate cancer cells. 30 3.9 Role of MTH in regulating AR signal pathway in castration-resistant prostate cancer cells. 31 3.10 MTH regulates androgen receptor (AR) signal pathway in castration resistant prostate cancer cells. 32 3.11 Androgens have no effects on the expression of MTH in human prostate cancer cells. 33 3.12 The mRNA levels of demethylase LSD1 in castration-resistant prostate cancer cells. 33 3.13 The levels of monomethylation at histone H3 lysine 4 (H3K4me) and demethylation at histone H3 lysine36 (H3K36me2) (two MTH-methylated sites) in castration-resistant prostate cancer cells. 34 Chapter 4. Discussion 36 Chapter 5. Figures 42 Chapter 6. References 72 | |
| dc.language.iso | en | |
| dc.subject | 組蛋白甲基化 | zh_TW |
| dc.subject | 抗荷爾蒙療法之攝護腺癌 | zh_TW |
| dc.subject | 甲基轉移? | zh_TW |
| dc.subject | 雄激素訊息傳遞路徑 | zh_TW |
| dc.subject | androgen receptor signaling pathway | en |
| dc.subject | histone methyltransferase | en |
| dc.subject | Methyltransferase H | en |
| dc.subject | castration-resistant prostate cancer | en |
| dc.title | 甲基轉移酶在攝護腺癌惡化過程作用機制之研究 | zh_TW |
| dc.title | Role of Methyltransferase in prostate cancer progression | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 鄧述諄(Shu-Chun Teng),黃祥博(Hsiang-Po Huang),華國泰(Kuo-Tai Hua) | |
| dc.subject.keyword | 抗荷爾蒙療法之攝護腺癌,組蛋白甲基化,甲基轉移?,雄激素訊息傳遞路徑, | zh_TW |
| dc.subject.keyword | castration-resistant prostate cancer,histone methyltransferase,Methyltransferase H,androgen receptor signaling pathway, | en |
| dc.relation.page | 77 | |
| dc.identifier.doi | 10.6342/NTU201702324 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-08-01 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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