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大学・研究所にある論文を検索できる 「高異型度卵巣漿液性癌における SMYD2 の機能解析および SMYD2 選択的阻害剤の治療効果の検討」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

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高異型度卵巣漿液性癌における SMYD2 の機能解析および SMYD2 選択的阻害剤の治療効果の検討

久木田, 麻子 東京大学 DOI:10.15083/0002007043

2023.03.24

概要

[課程-2]
審査の結果の要旨
氏名 久木田 麻子
本研究は、リシンメチル化酵素 SMYD2 が PARP1 の 528 番目のリシン基をメチル化し
PARP1 を活性化することに着目し、高異型度卵巣漿液性癌(HGSOC)に対して、
SMYD2 が新規治療標的になり得るか、SMYD2 選択的阻害剤(LLY-507)の単剤療法お
よび卵巣癌の維持療法として承認されている PARP(Poly(ADP-ribose) polymerase)阻害
剤(オラパリブ)との併用療法が新規治療戦略となり得るか検証し、下記の結果を得てい
る。
1. HGSOC の新鮮凍結検体を使用してリアルタイム PCR 法を行った結果、6 種類のヒス
トンメチル化酵素(SMYD2、EZH2、WHSC1、SUV39H2、SETD7、SETD1A)の有意
な発現亢進が認められた(p<0.01)
2. HGSOC の FFPE 切片を使用して免疫組織化学染色を行った結果、SMYD2 の有意な発
現亢進が認められた(p<0.0001)。
3. HGSOC 細胞株(JHOS3 細胞、KURAMOCHI 細胞)に対して、siRNA による
SMYD2 のノックダウンおよび LLY-507 単剤療法により、細胞生存アッセイ、細胞周期解
析、ウェスタンブロット法、コロニー形成試験を行った結果、有意な細胞増殖抑制、コロ
ニー形成抑制、アポトーシス誘導が認められた(p<0.05)。
4. LLY-507 とオラパリブの併用療法により、相加効果が認められた(p<0.01)。
以上、本論文は、HGSOC に対して、SMYD2 の抑制により細胞増殖抑制およびアポトー
シスが認められること、LLY-507 単剤療法により抗腫瘍効果が認められること、LLY-507
とオラパリブの併用療法により相加効果が認められることを明らかにした。
本研究は、LLY-507 単剤もしくはオラパリブとの併用療法が、卵巣癌に対する新規治療薬
となり得る可能性、既存の化学療法・維持療法の効果を上乗せする可能性、薬剤・放射線
感受性を高める可能性が示唆され、今後の卵巣癌治療の発展に貢献をなすと考えられる。
よって本論文は博士(医学 )の学位請求論文として合格と認められる。

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参考文献

[1] Bray F, et al. Global cancer statistics 2018: GLOBOCAN estimates of

incidence and mortality worldwide for 36 cancers in 185 countries. CA

Cancer J Clin. 2018;68:394-424.

[2] Rosendhal M, et al. Restaging and survival analysis of 4036 ovarian

cancer patients according to the 2013 FIGO classification for ovarian,

fallopian tube and primary peritoneal cancer. Int J Gynecol Cancer.

2016;26:680-687.

[3] LC Peres, et al. Invasive epithelial ovarian cancer survival by

histotype and disease stage. J Natl Cancer Inst. 2019;111:60-68.

[4] Stephanie L, et al. Epithelial Ovarian Cancer: Evolution of Management

in the Era of Precision Medicine. CA CANCER J CLIN. 2019;69:280–304.

[5] 榎本隆之. 日本産科婦人科学会婦人科腫瘍委員会報告. 第 59 回治療年報. 日産

婦誌 2018;70:1372-1444.

[6] 国立がん研究センターがん対策情報センター がん登録・統計. (2020)

http://gdb.ganjoho.jp/graph_db/

[7] 榎本隆之. 日本産科婦人科学会婦人科腫瘍委員会報告. 第 59 回治療年報. 日産

婦誌 2018;70:1372-1444.

[8] 卵巣がん・卵管癌・腹膜癌治療ガイドライン 2020 年版、金原出版

56

[9] 榎本隆之. 日本産科婦人科学会婦人科腫瘍委員会報告. 2017 年度患者年報. 日

産婦誌 2019;71:669-724.

[10] R. J. Kurman. Origin and molecular pathogenesis of ovarian high-grade

serous carcinoma. Annals of Oncology 24 (Supplement 10): x16–x21, 2013

doi:10.1093/annonc/mdt463.

[11] Labidi-Galy SI, et al. High grade serous ovarian carcinomas originate

in the fallopian tube. Nat Commun. 2017;8:1093.

[12] Lee, Y. et al. A candidate precursor to serous carcinoma that

originates in the distal fallopian tube. J. Pathol. 211, 26–35 (2007).

[13] Kindelberger DW, et al. Intraepithelial carcinoma of the fimbria and

pelvicserous carcinoma : evidence for a causal relationship. Am. J. Surg.

Pathol. 31,161–169 (2007).

[14] Cancer Genome Atlas Research Network. Integrated genomic analyses of

ovarian carcinoma. Nature. 2011 Jun 29;474(7353):609-15.

doi:10.1038/nature10166.

[15] Ksenija N, et al. Targeting DNA repair: the genome as a potential

biomarker. J Pathol 2018; 244: 586–597.

57

[16] Walsh T, et al. Detection of inherited mutations for breast and

ovarian cancer using genomic capture and massively parallel sequencing.

Proc Natl Acad Sci U S A. 2010;107:12629-12633.

[17] Karoline B K, et al. Risks of Breast, Ovarian, and Contralateral

Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA. 2017 Jun

20;317(23):2402-2416.

doi: 10.1001/jama.2017.7112.

[18] Nasim M, et al. Cancer risks for BRCA1 and BRCA2 mutation carriers:

results from prospective analysis of EMBRACE. Cancer Inst. 2013 Jun

5;105(11):812-22.

doi: 10.1093/jnci/djt095.

[19] Collins N, et al. Absence of methylation of CpG dinucleotides within

the promoter of the breast cancer susceptibility gene BRCA2 in normal

tissues and in breast and ovarian cancers. BrJ Cancer 1997; 76: 1150–1156.

[20] MS Piver, et al. Treatment of ovarian cancer at the crossroads: 50

years after single-agent melphalan chemotherapy. Oncology (Williston Park).

2006;20:1156,1158.

[21] Eric L, et al. The effect of maximal surgical cytoreduction on

sensitivity to platinum-taxane chemotherapy and subsequent survival in

patients with advanced ovarian cancer. Gynecologic Oncology 108 (2008) 276–

281

58

[22] Karam A, et al. Fifth Ovarian Cancer Consensus Conference of the

Gynecologic Cancer InterGroup: first-line interventions. Ann Oncol.

2017;28:711-717.

[23] MK Wilson, D Aoki, et al. Fifth Ovarian Cancer Consensus Conference of

the Gynecologic Cancer InterGroup: recurrent disease. Ann Oncol.

2017;28:727-732.

[24] McGee J, et al. Fifth Ovarian Cancer Consensus Conference:

individualized therapy and patient factors. Ann Oncol. 2017;28:702-710.

[25] https://www.astrazeneca.co.jp/media/press-releases1/2020/20201228

02.html

[26] https://www.takeda.com/ja-jp/announcements/2020/parp2/

[27]

Jennine M.D, et al. PARP-1 Activation Requires Local Unfolding of an

Autoinhibitory Domain. Molecular Cell 60, 755–768, December 3, 2015.

[28] Levani Z, et al. Structural basis for allosteric PARP-1 retention

on DNA breaks. Science 368, eaax6367 (2020). DOI: 10.1126/science.aax6367.

[29] Junko M, et al. Trapping of PARP1 and PARP2 by Clinical PARP

Inhibitors. Cancer Res; 72(21) November 1, 2012.

[30] Michèle R, et al. PARP inhibition: PARP1 and beyond. Nat Rev Cancer

10: 293–301 (2010). doi:10.1038/nrc2812.

59

[31] Thomas H. The underlying mechanism for the PARP and BRCA synthetic

lethality: Clearing up the misunderstandings. Molecular Oncology (2011)

387-393. doi:10.1016/j.molonc.2011.07.001.

[32] Helleday T, et al. DNA repair pathways as targets for cancer therapy.

Nature Rev Cancer. 2008;8:193-204.

[33] Murai J, et al. Trapping of PARP1 and PARP2 by clinical PARP

inhibitors. Cancer Res. 2012;72:5588-5599.

[34] Gelmon KA, et al. Olaparib in patients with recurrent high-grade

serous or poorly differentiated ovarian carcinoma or triple-negative breast

cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet

Oncol 2011;12:852-861. Available at: http://www.ncbi.nlm.nih.gov/pubmed/

21862407.

[35] Elit L, et al. Palliative systemic therapy for women with recurrent

epithelial ovarian cancer: current options. Onco Targets Ther 2013;6:107118. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23459506.

[36] Suh DH, et al. Major clinical research advances in gynecologic cancer

in 2014. J Gynecol Oncol 2015;26:156-167. Available at:

http://www.ncbi.nlm.nih.gov/pubmed/25872896.

60

[37] Pujade-Lauraine E, et al. Olaparib tablets as maintenance therapy in

patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2

mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebocontrolled, phase 3 trial. Lancet Oncol 2017;18:1274-1284. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/28754483.

[38] Fong PC, et al. Poly(ADP)-ribose polymerase inhibition: frequent

durable responses in BRCA carrier ovarian cancer correlating with platinumfree interval. J Clin Oncol 2010;28:2512-2519. Available at:

http://www.ncbi.nlm.nih.gov/pubmed/20406929.

[39] Ledermann J, et al. Olaparib maintenance therapy in platinum-sensitive

relapsed ovarian cancer. N Engl J Med 2012;366:1382-1392. Available at:

http://www.ncbi.nlm.nih.gov/pubmed/22452356.

[40] National Comprehensive Cancer Network. NCCN clinical practice

guidelines in oncology: ovarian cancer version 1. 2020

(https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf).

[41] AstraZeneca. Lynparza (olaparib) tablets, for oral use: prescribing

information. 2018 (https://www.accessdata.fda.gov/drugsatfda _docs/label/

2018/208558s001lbl.pdf).

61

[42] MR Mirza, et al. Niraparib maintenance therapy in platinum-sensitive,

recurrent ovarian cancer. N Engl J Med 2016;375:2154-2164.

[43] MR Mirza, et al. Niraparib plus bevacizumab versus niraparib alone for

platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a

randomised, phase 2,superiority trial. Lancet Oncol 2019; 20: 1409–19

[44] Christoph P, et al. Mutations in regulators of the epigenome and their

connections to global chromatin patterns in cancer. Nat Rev Genet 14: 765–

780.doi:10.1038/nrg3554

[45] Stephen B, et al. A decade of exploring the cancer epigenome—

biological and translational implications. Nat Rev Cancer 11: 726–734.

doi:10.1038/nrc3130

[46] Jones P. A. & Baylin S. B. The fundamental role of epigenetic events

in cancer. Nature Rev. Genet. 3, 415–428 (2002).

[47] Jones P. A. & Baylin S. B. The epigenomics of cancer. Cell 128, 683–

692 (2007).

[48] Esteller M. Epigenetics in cancer. N. Engl. J. Med. 358, 1148–1159

(2008).

62

[49] Y Saito, et al. Specific activation of microRNA‑127 with

downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in

human cancer cells. Cancer Cell 9, 435–443 (2006).

[50] Luger K, et al. Nucleosome and chromatin fiber dynamics. Curr Opin

Struct Biol 2005; 15: 188–196.

[51] B.D. Strahl, et al. The language of covalent histone modifications,

Nature 403 (2000) 41e45. https://doi.org/10.1038/47412.

[52] Greer EL & Shi Y. Histone methylation: a dynamic mark in health,

disease and inheritance. Nature Rev. Genet. 13, 343–357 (2012).

[53] Xi Zhang, et al. Emerging roles of lysine methylation on non-histone

proteins. Cell. Mol. Life Sci. (2015) 72:4257–4272. DOI 10.1007/s00018-0152001-4.

[54] Kyle K, et al. Non-histone protein methylation as a regulator of

cellular signalling and function. Nat Rev Mol Cell Bio 16: 5–17.

doi:10.1038/nrm3915.

[55] Black JC, et al. Histone lysine methylation dynamics: establishment,

regulation, and biological impact. Mol Cell 2012; 48: 491–507.

[56] Wagner EJ, et al. Understanding the language of Lys36 methylation at

histone H3. Nat Rev Mol Cell Biol 2012; 13: 115–126.

63

[57] Kwangbeom Hyun, et al. Writing, erasing and reading histone lysine

methylations. Exp & Mol Medi (2017) 49, e324; doi:10.1038/emm.2017.11.

[58] Paik WK, et al. Historical review: the field of protein methylation.

Trends Biochem. Sci. 32, 146–152 (2007).

[59] Kouzarides T. Histone methylation in transcriptional control. Curr

Opin Genet Dev (2002) 12(2):198–209 4.

[60] Zhou VW, et al. Charting histone modifications and the functional

organization of mammalian genomes. Nature Rev. Cancer 12, 7–18 (2011).

[61] Bannister AJ & Kouzarides T. Regulation of chromatin by histone

modifications. Cell Res. 21, 381–395 (2011)

[62] RJ Sims 3rd, et al. Histone lysine methylation: a signature for

chromatin function. Trends Genet (2003) 19(11):629–639 5.

[63] Martin C, et al. The diverse functions of histone lysine methylation.

Nat Rev Mol Cell Biol (2005) 6(11):838–849.

[64] Sabbattini P, et al. An H3K9/S10 methyl-phospho switch modulates

Polycomb and Pol II binding at repressed genes during differentiation. Mol.

Biol. Cell. 25, 904–915 (2014).

64

[65] Levy D. et al. Lysine methylation of the NF‑κB subunit RelA by SETD6

couples activity of the histone methyltransferase GLP at chromatin to tonic

repression of NF‑κB signaling. Nature Immunol. 12, 29–36 (2011).

[66] Xie Q, et al. Methylation-mediated regulation of E2F1 in DNA damageinduced cell death. J. Recept. Signal Transduct. Res. 31, 139–146 (2011).

[67] Botuyan MV, et al. Structural basis for the methylation state-specific

recognition of histone H4‑K20 by 53BP1 and Crb2 in DNA repair. Cell 127,

1361–1373 (2006).

[68] Dhayalan A, et al. Specificity analysis-based identification of new

methylation targets of the SET7/9 protein lysine methyltransferase. Chem.

Biol. 18, 111–120 (2011).

[69] Kwak YT, et al. Methylation of SPT5 regulates its interaction with RNA

polymerase II and transcriptional elongation properties. Mol. Cell 11,

1055–1066 (2003).

[70] Rho J, et al. Arginine methylation of Sam68 and SLM proteins

negatively regulates their poly(U) RNA binding activity. Arch. Biochem.

Biophys. 466, 49–57 (2007).

[71] Swiercz R, et al. Ribosomal protein rpS2 is hypomethylated in

PRMT3‑deficient mice. J. Biol. Chem. 282, 16917–16923 (2007).

65

[72] Carr SM, et al. Interplay between lysine methylation and Cdk

phosphorylation in growth control by the retinoblastoma protein. EMBO J.

30, 317–327 (2011).

[73] Martin G, et al. Arginine methylation in subunits of mammalian premRNA cleavage factor I. RNA 16, 1646–1659 (2010).

[74] Mazur PK, et al. SMYD3 links lysine methylation of MAP3K2 to Rasdriven cancer. Nature 510, 283–287 (2014).

[75] Lu R & Wang G, G Tudor. A versatile family of histone methylation

‘readers’. Trends Biochem. Sci. 38, 546–555 (2013).

[76] Gayatri S & Bedford MT. Readers of histone methylarginine marks.

Biochim. Biophys. Acta 1839, 702–710 (2014).

[77] Musselman CA, et al. Towards understanding methyllysine readout.

Biochim Biophys Acta 2014; 1839: 686–693.

[78] M Abu-Farha, et al. The tale of two domains: proteomics and genomics

analysis of SMYD2, a new histone methyltransferase. Mol Cell Proteomics,

2008, 7, 560–572.

[79] MA Brown, et al. Identification and characterization of Smyd2: a split

SET/MYND domain-containing histone H3 lysine 36-specific methyltransferase

66

that interacts with the Sin3 histone deacetylase complex. Mol. Cancer 5

(2006) 26. https://doi.org/10.1186/1476-4598-5-26.

[80] Xu G, et al. The histone methyltransferase Smyd2 is a negative

regulator of macrophage activation by suppressing interleukin 6 (IL-6) and

tumor necrosis factor α (TNF-α) production. J. Biol. Chem. 290(9), 5414–

5423 (2015).

[81] J Huang, et al. Repression of p53 activity by Smyd2-mediated

methylation, Nature 444 (2006) 629e632. https://doi.org/10.1038/nature

05287.

[82] HS Cho, et al. RB1 methylation by SMYD2 enhances cell cycle

progression through an increase of RB1 phosphorylation. Neoplasia, 14,

2012, 476e486. https://doi.org/10.1593/neo.12656.

[83] L Piao, et al. The histone methyltransferase SMYD2 methylates PARP1

and promotes poly(ADP-ribosyl)ation activity in cancer cells, Neoplasia 16

(2014) 257e264. https://doi.org/10.1016/j.neo.2014.03.002.

[84] R Hamamoto, et al. SMYD2-dependent HSP90 methylation promotes cancer

cell proliferation by regulating the chaperone complex formation, Cancer

Lett. 351 (2014) 126e133. https://doi.org/10.1016/j.canlet.2014.05.014.

67

[85] X Zhang, et al. Regulation of estrogen receptor α by histone

methyltransferase SMYD2‑mediated protein methylation. Proc. Natl Acad. Sci.

USA 110,17284–17289 (2013).

[86] R Wang, et al. Effects of SMYD2-mediated EML4-ALK methylation on the

signaling pathway and growth in non-small-cell lung cancer cells. Cancer

Sci. 108 (2017) 1203e1209. https://doi.org/10.1111/cas.13245.

[87]

Xiaolan D, et al. Critical roles of SMYD2-mediated b-catenin

methylation for nuclear translocation and activation of Wnt signaling.

Oncotarget 8 (2017) 55837e55847, https://doi.org/10.18632/oncotarget.19646.

[88] M Nakakido, et al. Dysregulation of AKT pathway by SMYD2-mediated

lysine methylation on PTEN, Neoplasia 17 (2015) 367e373.

https://doi.org/10.1016/j.neo.2015.03.002.

[89] N Reynoird, et al. Coordination of stress signals by the lysine

methyltransferase SMYD2 promotes pancreatic cancer. Genes Dev. 2016 Apr

1;30(7):772-85.

doi: 10.1101/gad.275529.115.

[90] LX Li, et al. Lysine methyltransferase SMYD2 promotes triple negative

breast cancer progression, Cell Death Dis. 9 (2018). https://doi.org/10.

1038/s41419-018-0347-x.

68

[91] Hannah N, et al. LLY-507, a Cell-active, Potent, and Selective

Inhibitor of Protein-lysine Methyltransferase SMYD2. THE JOURNAL OF

BIOLOGICAL CHEMISTRY VOL.290, NO.22, pp. 13641–13653, May 29, 2015.

[92] Yi Z, et al. Regulation of EZH2 by SMYD2-Mediated Lysine Methylation

Is Implicated in Tumorigenesis. Cell Reports 29, 1482–1498, November 5,

2019. https://doi.org/10.1016/j.celrep.2019.10.004.

[93] Fanchao M, et al. SMYD2 suppresses APC2 expression to activate the

Wnt/β-catenin pathway and promotes epithelial-mesenchymal transition in

colorectal cancer.

[94] Chen, A. PARP inhibitors: its role in treatment of cancer. Chin. J.

Cancer 30, 463–471 (2011).

[95] R Hamamoto, et al. Critical roles of non-histone protein lysine

methylation in human tumorigenesis, Nat Publ. Gr. 15 (2015) 110-124.

https://doi.org/10.1038/nrc3884.

[96] L Yan, et al. Inhibition of SMYD2 suppresses tumor progression by

down-regulating microRNA-125b and attenuates multi-drug resistance in renal

cell carcinoma. Theranostics.2019,Oct,22;9(26):8377-8391. doi:10.7150/thno.

37628.

69

[97] M Kojima, et al. The histone methyltransferase SMYD2 is a novel

therapeutic target for the induction of apoptosis in ovarian clear cell

carcinoma cells. Oncol Lett. 2020 Nov;20(5):153.

doi: 10.3892/ol.2020.

12014.

[98] JJ Sun, et al. SMYD2 promotes cervical cancer growth by stimulating

cell proliferation. Cell Biosci. 2019 Sep 18;9:75. doi:10.1186/s13578-0190340-9.

[99] S Komatsu, et al. Overexpression of SMYD2 relates to tumor cell

proliferation and malignant outcome of esophageal squamous cell carcinoma.

Carcinogenesis 30, 1139–1146 (2009).

[100] S Komatsu, et al. Overexpression of SMYD2 contributes to malignant

outcome in gastric cancer. Br. J. Canc. 112 (2015)357-364.

https://doi.org/10.1038/bjc.2014.543.

[101] LHT Sakamoto, et al. SMYD2 is highly expressed in pediatric acute

lymphoblastic leukemia and constitutes a bad prognostic factor. Leuk Res.

2014 Apr;38(4):496-502.

doi: 10.1016/j.leukres.2014.01.013.

[102] Shan-Ru Z, et al. Positive Expression of SMYD2 is Associated with

Poor Prognosis in Patients with Primary Hepatocellular Carcinoma. 2018;

9(2): 321-330. doi: 10.7150/jca.22218.

70

[103] S Ooki, et al. Oncogenic histone methyltransferase EZH2: a novel

prognostic marker with therapeutic potential in endometrial cancer,

Oncotarget 8 (2017) 40402e40411, https://doi.org/10.18632/oncotarget.16316.

[104] T Fukuda, et al. The anti-malarial chloroquine suppresses

proliferation and overcomes cisplatin resistance of endometrial cancer

cells via autophagy inhibition, Gynecol. Oncol. 137 (2015) 538e545.

https://doi.org/10.1016/j.ygyno.2015.03.053.

[105] Y Li, et al. Elevated expression of CXC chemokines in pediatric

osteosarcoma patients, Cancer 117 (2011) 207e217, https://doi.org/10.1002/

cncr.25563.

[106] SH Jang, et al. High EZH2 protein expression is associated with poor

overall survival in patients with luminal a breast cancer, J B

Can19(2016)53e60. https://doi.org/10.4048/jbc.2016.19.1.53.

[107] A Vaidyanathan, et al. ABCB1 (MDR1) induction defines a common

resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer

cellsBr J Cancer. 2016 Aug 9;115(4):431-41.

doi: 10.1038/bjc.2016.203.

[108] Peralta-Leal A, et al. Poly(ADP-ribose) polymerase-1 (PARP-1) in

carcinogenesis: potential role of PARP inhibitors in cancer treatment. Clin

Transl Oncol 10, 318–323 (2008).

71

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