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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李財坤(Tsai-Kun Li) | |
| dc.contributor.author | Yu-Cheng Lin | en |
| dc.contributor.author | 林煜錚 | zh_TW |
| dc.date.accessioned | 2022-11-24T03:13:12Z | - |
| dc.date.available | 2021-11-03 | |
| dc.date.available | 2022-11-24T03:13:12Z | - |
| dc.date.copyright | 2021-11-03 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-10-19 | |
| dc.identifier.citation | 1. Sung, H, Ferlay, J, Siegel, RL, Laversanne, M, Soerjomataram, I, Jemal, A, Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2020 2. Feldman, B., Feldman, D. The development of androgen-independent prostate cancer. Nat Rev Cancer 1, 34–45 (2001). 3. Swami U, McFarland TR, Nussenzveig R, Agarwal N. Advanced Prostate Cancer: Treatment Advances and Future Directions. Trends Cancer. 2020;6(8):702-715. 4. Griffin, J. E. Wilson, J. D. in Williams Testbook of Endocrinology 9th edn (eds Wilson, J. D., Foster, D. W., Kronenberg, H. M. Larsen, P. R.) 819–876 (W. B. Saunders Co., Philadelphia, 1998). 5. Brinkmann, A. O. et al. Mechanisms of androgen receptor activation and function. J. Steroid Biochem. Mol. Biol. 69, 307–313 (1999). 6. Saraon P, Jarvi K, Diamandis EP. Molecular alterations during progression of prostate cancer to androgen independence. Clin Chem. 2011;57(10):1366-1375. 7. Wang Q, Li W, Zhang Y, et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell. 2009;138(2):245-256. 8. Lamb AD, Massie CE, Neal DE. The transcriptional programme of the androgen receptor (AR) in prostate cancer. BJU Int. 2014;113(3):358-366. 9. Ishizaki, F., Nishiyama, T., Kawasaki, T. et al. Androgen deprivation promotes intratumoral synthesis of dihydrotestosterone from androgen metabolites in prostate cancer. Sci Rep 3, 1528 (2013). 10. Visakorpi T, Hyytinen E, Koivisto P, et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet. 1995;9(4):401-406. 11. Tan J, Sharief Y, Hamil KG, et al. Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol. 1997;11(4):450-459. 12. Watson PA, Chen YF, Balbas MD, et al. Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci U S A. 2010;107(39):16759-16765. 13. Wen Y, Hu MC, Makino K, et al. HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res. 2000;60(24):6841-6845. 14. McDonnell TJ, Troncoso P, Brisbay SM, et al. Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res. 1992;52(24):6940-6944. 15. Craft N, Chhor C, Tran C, et al. Evidence for clonal outgrowth of androgen-independent prostate cancer cells from androgen-dependent tumors through a two-step process. Cancer Res. 1999;59(19):5030-5036. 16. Baylin SB, Jones PA. Epigenetic Determinants of Cancer. Cold Spring Harb Perspect Biol. 2016;8(9):a019505. 17. Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 2011;469(7330):343-349. 18. Kleer CG, Cao Q, Varambally S, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci U S A. 2003;100(20):11606-11611. 19. Raman JD, Mongan NP, Tickoo SK, Boorjian SA, Scherr DS, Gudas LJ. Increased expression of the polycomb group gene, EZH2, in transitional cell carcinoma of the bladder. Clin Cancer Res. 2005;11(24 Pt 1):8570-8576. 20. Sudo T, Utsunomiya T, Mimori K, et al. Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma. Br J Cancer. 2005;92(9):1754-1758. 21. Zingg, D., Debbache, J., Schaefer, S. et al. The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors. Nat Commun 6, 6051 (2015). 22. Varambally S, Dhanasekaran SM, Zhou M, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002;419(6907):624-629. 23. Gan, L., Yang, Y., Li, Q. et al. Epigenetic regulation of cancer progression by EZH2: from biological insights to therapeutic potential. Biomark Res 6, 10 (2018). 24. Horoszewicz JS, Leong SS, Kawinski E, et al. LNCaP model of human prostatic carcinoma. Cancer Res. 1983;43(4):1809-1818. 25. Culig Z, Hoffmann J, Erdel M, et al. Switch from antagonist to agonist of the androgen receptor bicalutamide is associated with prostate tumour progression in a new model system. Br J Cancer. 1999;81(2):242-251. 26. Xu K, Wu ZJ, Groner AC, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science. 2012;338(6113):1465-1469. 27. Champoux, J. J. DNA topoisomerases: structure, function, and mechanism. Annu. Rev. Biochem. 70, 369–413 (2001). 28. Villman K, Ståhl E, Liljegren G, Tidefelt U, Karlsson MG. Topoisomerase II-alpha expression in different cell cycle phases in fresh human breast carcinomas. Mod Pathol. 2002;15(5):486-491. 29. Woessner RD, Mattern MR, Mirabelli CK, Johnson RK, Drake FH. Proliferation- and cell cycle-dependent differences in expression of the 170 kilodalton and 180 kilodalton forms of topoisomerase II in NIH-3T3 cells. Cell Growth Differ. 1991;2(4):209-214. 30. Wong RH, Chang I, Hudak CS, Hyun S, Kwan HY, Sul HS. A role of DNA-PK for the metabolic gene regulation in response to insulin. Cell. 2009;136(6):1056-1072. 31. Trotter KW, King HA, Archer TK. Glucocorticoid Receptor Transcriptional Activation via the BRG1-Dependent Recruitment of TOP2β and Ku70/86. Mol Cell Biol. 2015;35(16):2799-2817. 32. Ju BG, Lunyak VV, Perissi V, et al. A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription. Science. 2006;312(5781):1798-1802. 33. Pflug BR, Reiter RE, Nelson JB. Caveolin expression is decreased following androgen deprivation in human prostate cancer cell lines. Prostate. 1999;40(4):269-273. 34. Nadiminty N, Tummala R, Liu C, et al. NF-κB2/p52 induces resistance to enzalutamide in prostate cancer: role of androgen receptor and its variants. Mol Cancer Ther. 2013;12(8):1629-1637. 35. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324(5928):787-790. 36. Haffner MC, Aryee MJ, Toubaji A, et al. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat Genet. 2010;42(8):668-675. 37. Oliviero G, Brien GL, Waston A, et al. Dynamic Protein Interactions of the Polycomb Repressive Complex 2 during Differentiation of Pluripotent Cells. Mol Cell Proteomics. 2016;15(11):3450-3460. 38. Ta HQ, Gioeli D. The convergence of DNA damage checkpoint pathways and androgen receptor signaling in prostate cancer. Endocr Relat Cancer. 2014;21(5):R395-R407. 39. Polkinghorn WR, Parker JS, Lee MX, et al. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov. 2013;3(11):1245-1253. 40. Vairapandi M, Azam N, Balliet AG, Hoffman B, Liebermann DA. Characterization of MyD118, Gadd45, and proliferating cell nuclear antigen (PCNA) interacting domains. PCNA impedes MyD118 AND Gadd45-mediated negative growth control. J Biol Chem. 2000;275(22):16810-16819. 41. He, Y., Wei, T., Ye, Z. et al. A noncanonical AR addiction drives enzalutamide resistance in prostate cancer. Nat Commun 12, 1521 (2021). 42. Kim J, Lee Y, Lu X, et al. Polycomb- and Methylation-Independent Roles of EZH2 as a Transcription Activator. Cell Rep. 2018;25(10):2808-2820.e4. 43. Duan, R., Du, W. Guo, W. EZH2: a novel target for cancer treatment. J Hematol Oncol 13, 104 (2020). 44. Wang X, Cao W, Zhang J, et al. A covalently bound inhibitor triggers EZH2 degradation through CHIP-mediated ubiquitination. EMBO J. 2017;36(9):1243-1260. 45. Li Z, Hou P, Fan D, et al. The degradation of EZH2 mediated by lncRNA ANCR attenuated the invasion and metastasis of breast cancer. Cell Death Differ. 2017;24(1):59-71. 46. Cha TL, Zhou BP, Xia W, et al. Akt-mediated phosphorylation of EZH2 suppresses methylation of lysine 27 in histone H3. Science. 2005;310(5746):306-310. 47. Bitting RL, Armstrong AJ. Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer. Endocr Relat Cancer. 2013;20(3):R83-R99. 48. Shorning BY, Dass MS, Smalley MJ, Pearson HB. The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling. Int J Mol Sci. 2020;21(12):4507. 49. Goodwin JF, Kothari V, Drake JM, et al. DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis. Cancer Cell. 2015;28(1):97-113. 50. Schiewer MJ, Goodwin JF, Han S, et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov. 2012;2(12):1134-1149. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/80695 | - |
| dc.description.abstract | "攝護腺癌發生率持續上升，至今已成為全球男性中第二常見的癌症，且目前並無有效的治療方式。EZH2蛋白作為Polycomb Repressive Complex 2 (PRC2)的重要成員，被認為是攝護腺癌進展過程中的一大關鍵。治療攝護腺癌常見的「荷爾蒙療法」，藉由移除人體內雄性激素的生成或阻斷對其的接收以達到抑制癌細胞生長的療程，雖然能讓多數病人病情暫時穩定好轉，然而腫瘤仍有很高機率會復發並進展成為「荷爾蒙抗性攝護腺癌」的型態。在此過程中，EZH2於S21位點被磷酸化(Phosphorylated EZH2 at serine 21, pS21 EZH2)的量有上升的現象，使其脫離原本的PRC2複合體，產生「EZH2介導的基因表現轉換(EZH2-mediated Switch of Gene Expression)」，即從抑制基因表現的角色，轉為活化下游另一類別的基因群體(Solo Gene Expression)，從而在不依賴雄性激素的情況下維持腫瘤的生長。有鑑於以往研究指出，在雄性激素受體(Androgen Receptor, AR)受到雄性激素刺激後所活化下游基因表現的過程中，需要有第IIB型拓樸異構酶(Topoisomerase IIβ, TOP2B)的參與。因此，本篇研究著重探討進展至荷爾蒙抗性型態的攝護腺癌中，由pS21 EZH2所主導的基因活化過程中，TOP2B是否直接或間接地參與其中分子的調控機轉。我們發現TOP2B在有無雄性激素的刺激下，皆會與pS21 EZH2產生蛋白質交互作用，並共同結合於solo genes上游啟動子(promoter)或增強子(enhancer)上，進而促進此途徑的活化及相關基因的表達。透過深入分析各類分子介導基因表現的調節機制，我們期望建立一系列更全面且有效治療荷爾蒙抗性攝護腺癌的標準療程。" | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-24T03:13:12Z (GMT). No. of bitstreams: 1 U0001-1810202115305500.pdf: 1341544 bytes, checksum: ad2dd2816395a51985b3c66aa20804a3 (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | 中文摘要 ......................................................................... I ABSTRACT ........................................................................ II INTRODUCTION - Prostate Cancer ............................................................... 1 - Androgen Receptor Signaling Pathway ........................................... 2 - Mechanisms of Androgen Resistance ............................................. 2 - Polycomb Repressive Complex 2 (PRC2) .......................................... 5 - EZH2-mediated Gene Expression Switch .......................................... 6 - Role of Topoisomerase IIβ in Nuclear Receptor-mediated Gene Transcription ..... 7 SPECIFIC AIM .................................................................... 9 MATERIALS METHODS ............................................................ 10 RESULTS 1. Elevated EZH2 Phosphorylation Level at Serine 21 in CRPC Cells .............. 17 2. Higher Expression of Solo Genes in CRPC Cells ............................... 19 3. Down-regulation of Solo Gene Expression upon TOP2B Silencing in CRPC Cells ... 19 4. TOP2B Physically Cooperates with Phosphorylated (S21) EZH2 in CRPC Cells ..... 20 5. Direct Binding of TOP2B for Transcriptional Activation around Solo Gene Promoter/Enhancer in CPRC Cells ............................................. 22 DISCUSSION ..................................................................... 24 TABLES FIGURES - Table 1. mRNA real-time RT-PCR primers ....................................... 27 - Table 2. Lentiviral shRNA sequences .......................................... 28 - Table 3. Chromatin Immunoprecipitation-qPCR primers .......................... 28 - Figure 1. Comparison of phosphorylated (S21) level of EZH2 and its expression among ADPC and CRPC Cells in the absence or presence of androgen ............. 29 - Figure 2. Confirmation of phosphorylated (S21) EZH2-mediated solo gene activation in castration-resistant prostate cancer cell lines ................ 31 - Figure 3. Requirement of TOP2B for transcriptional activation of solo genes in castration-resistant prostate cancer cell lines ........................... 32 - Figure 4. Protein interaction between TOP2B and phosphorylated (S21) EZH2 in CRPC cell lines ........................................................... 34 - Figure 5. Enrichment of TOP2B Chromatin Binding Signals around promoter or enhancer regions of Solo Genes in CPRC cell lines ............................ 36 REFERENCES ..................................................................... 38 | |
| dc.language.iso | en | |
| dc.subject | Solo Gene表達 | zh_TW |
| dc.subject | 荷爾蒙療法 | zh_TW |
| dc.subject | S21位點磷酸化EZH2 | zh_TW |
| dc.subject | 第IIB型拓樸異構酶 | zh_TW |
| dc.subject | 荷爾蒙抗性攝護腺癌 | zh_TW |
| dc.subject | Phosphorylated (S21) Enhancer of Zeste Homolog 2 (pS21-EZH2) | en |
| dc.subject | Topoisomerase IIβ (TOP2B) | en |
| dc.subject | Castration-Resistant Prostate Cancer (CRPC) | en |
| dc.subject | Androgen-Deprivation Therapy (ADT) | en |
| dc.subject | Solo Gene Expression | en |
| dc.title | DNA第IIB型拓樸異構酶在荷爾蒙抗性攝護腺癌中對EZH2磷酸化後介導Solo Gene表現的調節機制 | zh_TW |
| dc.title | DNA Topoisomerase IIβ Regulates the EZH2-mediated Expression of Solo Genes in Castration-Resistant Prostate Cancer | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 黃昭淵(Hsin-Tsai Liu),李明學(Chih-Yang Tseng) | |
| dc.subject.keyword | 荷爾蒙抗性攝護腺癌,荷爾蒙療法,S21位點磷酸化EZH2,第IIB型拓樸異構酶,Solo Gene表達, | zh_TW |
| dc.subject.keyword | Castration-Resistant Prostate Cancer (CRPC),Androgen-Deprivation Therapy (ADT),Phosphorylated (S21) Enhancer of Zeste Homolog 2 (pS21-EZH2),Topoisomerase IIβ (TOP2B),Solo Gene Expression, | en |
| dc.relation.page | 42 | |
| dc.identifier.doi | 10.6342/NTU202103830 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2021-10-20 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 微生物學研究所 | zh_TW |
| 顯示於系所單位： | 微生物學科所 | |
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