您的位置：山东大学 -> 科技期刊社 -> 《山东大学学报（医学版）》

山东大学学报 (医学版) ›› 2020, Vol. 58 ›› Issue (8): 88-94.doi: 10.6040/j.issn.1671-7554.0.2020.0604

• 脑科学与类脑智能研究专题 • 上一篇    下一篇

靶向小类泛素化修饰的胶质瘤治疗新策略

陈安静1,2,*(),张训1,2   

  1. 1. 山东大学齐鲁医院神经外科，山东大学脑与类脑科学研究院, 山东 济南 250012
    2. 山东省脑功能重构重点实验室, 山东 济南 250012
  • 收稿日期:2020-04-15 出版日期:2020-08-01 发布日期:2020-08-07
  • 通讯作者: 陈安静 E-mail:chenaj@sdu.edu.cn
  • 作者简介:陈安静，研究员，山东省“泰山学者”青年专家，山东大学生物化学与分子生物学博士。研究方向为SUMO化和泛素化修饰调控脑胶质瘤恶性进展与转化的分子机制。以项目负责人身份主持国家自然科学基金、中国博士后基金面上项目、山东省重点研发计划和山东省自然科学基金等。累计发表SCI收录论文40篇，以通讯作者和第一作者在《Clinical Cancer Research》《Journal of Virology》等期刊发表文章。曾获山东省优秀科技创新成果奖、山东省医学科技奖和山东大学学生“五·四”青年科学奖等。
  • 基金资助:
    山东省泰山学者人才工程(tsqn201909173);中国博士后基金(2018M642666)

The new strategies of targeting SUMOylation in the treatment of glioma

Anjing CHEN1,2,*(),Xun ZHANG1,2   

  1. 1. Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China
    2. Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
  • Received:2020-04-15 Online:2020-08-01 Published:2020-08-07
  • Contact: Anjing CHEN E-mail:chenaj@sdu.edu.cn

RichHTML

8

PDF (PC)

481

摘要：

蛋白质的小类泛素(SUMO)化修饰(SUMOylation)是一种动态的翻译后修饰，涉及了细胞一系列的生理过程。值得注意的是，SUMO化也在多种癌症病理过程中发挥重要作用，其中包括严重危害人类健康的脑胶质瘤。本文回顾分析SUMO化修饰与胶质瘤相关的核心文献，着重探究SUMO化修饰过程中的关键靶点，可望作为胶质瘤治疗有潜力的新方法，为其精准靶向治疗提供新的策略。

关键词: 胶质瘤, 小类泛素化修饰, 恶性进展, 靶向治疗

Abstract:

Small ubiquitin-like modification (SUMOylation), a dynamic process of post-translational modification, involves a series of physiological changes within the cells. SUMOylation also plays an important role in the pathological progresses of a number of cancers including the fatal disease, glioma. In this essay, we reviewed the key aspects of SUMOylation in association with glioma from the literatures and highlighted that some potential targets were expected to be therapeutic strategies in the treatment of glioma.

Key words: Glioma, SUMOylation, Malignant progression, Targeted therapy

中图分类号: 

  • R456

图1

胶质瘤SUMO化修饰增强参与调节多重细胞过程并导致恶性进展"

1 Stupp R , Hegi ME , Mason WP , et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III study: 5-year analysis of the EORTC-NCIC trial[J]. Lancet Oncol, 2009, 10 (5): 459- 466.
doi: 10.1016/S1470-2045(09)70025-7
2 Polivka JJr , Polivka J , Holubec L , et al. Advances in experimental targeted therapy and immunotherapy for patients with glioblastoma multiforme[J]. Anticancer Res, 2017, 37 (1): 21- 33.
3 Mahajan R , Delphin C , Guan T , et al. A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2[J]. Cell, 1997, 88 (1): 97- 107.
doi: 10.1016/S0092-8674(00)81862-0
4 Hendriks I A , Vertegaal A C . A comprehensive compilation of SUMO proteomics[J]. Nat Rev Mol Cell Biol, 2016, 17 (9): 581- 595.
doi: 10.1038/nrm.2016.81
5 Eifler K , Vertegaal ACO . SUMOylation-mediated regulation of cell cycle progression and cancer[J]. Trends Biochem. Sci, 2015, 40 (12): 779- 793.
doi: 10.1016/j.tibs.2015.09.006
6 Bayer P , Arndt A , Metzger S , et al. Structure determination of the small ubiquitin-related modifier SUMO-1[J]. J Mol Biol, 1998, 280 (2): 275- 286.
doi: 10.1006/jmbi.1998.1839
7 Shen Z , Pardington-Purtymun PE , Comeaux JC , et al. UBL1, a human ubiquitin-like protein associating with human RAD51/RAD52 proteins[J]. Genomics, 1996, 36 (2): 271- 279.
doi: 10.1006/geno.1996.0462
8 Boddy MN , Howe K , Etkin LD , et al. PIC 1, a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukemia[J]. Oncogene, 1996, 13 (5): 971- 982.
9 Matunis MJ , Coutavas E , Blobel G . A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex[J]. J Cell Biol, 1996, 135 (6 Pt 1): 1457- 1470.
10 Lapenta V , Chiurazzi P , van der Spek P , et al. SMT3A, a human homologue of the S. cerevisiae SMT3 gene, maps to chromosome 21qter and defines a novel gene family[J]. Genomics, 1997, 40 (2): 362- 366.
doi: 10.1006/geno.1996.4556
11 Johnson ES . Protein modification by SUMO[J]. Annu Rev Biochem, 2004, 73: 355- 382.
doi: 10.1146/annurev.biochem
12 Evdokimov E , Sharma P , Lockett SJ , et al. Loss of SUMO1 in mice affects RanGAP1 localization and formation of PML nuclear bodies, but is not lethal as it can be compensated by SUMO2 or SUMO3[J]. J Cell Sci, 2008, 121 (Pt 24): 4106- 4113.
13 Owerbach D , McKay EM , Yeh ET , et al. A proline-90 residue unique to SUMO-4 prevents maturation and sumoylation[J]. Biochem Biophys Res Commun, 2005, 337 (2): 517- 520.
doi: 10.1016/j.bbrc.2005.09.090
14 Hickey CM , Wilson NR , Hochstrasser M . Function and regulation of SUMO proteases[J]. Nat Rev Mol Cell Biol, 2012, 13 (12): 755- 766.
doi: 10.1038/nrm3478
15 Olsen SK , Capili AD , Lu X , et al. Active site remodelling accompanies thioester bond formation in the SUMO E1[J]. Nature, 2010, 463 (7283): 906- 912.
doi: 10.1038/nature08765
16 Gong L , Kamitani T , Fujise K , et al. Preferential interaction of sentrin with a ubiquitin-conjugating enzyme, Ubc9[J]. J Biol Chem, 1997, 272 (45): 28198- 28201.
doi: 10.1074/jbc.272.45.28198
17 Desterro JM , Thomson J , Hay RT . Ubch9 conjugates SUMO but not ubiquitin[J]. FEBS Lett, 1997, 417 (3): 297- 300.
doi: 10.1016/S0014-5793(97)01305-7
18 Rodriguez MS , Dargemont C , Hay RT . SUMO-1conjugation in vivo requires both a consensus modification motif and nuclear targeting[J]. J Biol Chem, 2001, 276 (16): 12654- 12659.
doi: 10.1074/jbc.M009476200
19 Johnson ES , Gupta AA . An E3-like factor that promotes SUMO conjugation to the yeast septins[J]. Cell, 2001, 106 (6): 735- 744.
doi: 10.1016/S0092-8674(01)00491-3
20 Gong L , Millas S , Maul GG , et al. Differential regulation of sentrinized proteins by a novel sentrin-specific protease[J]. J Biol Chem, 2000, 275 (5): 3355- 3359.
doi: 10.1074/jbc.275.5.3355
21 Schulz S , Chachami G , Kozaczkiewicz L , et al. Ubiquitin-specific protease-like 1(USPL1) is a SUMO isopeptidase with essential, non-catalytic functions[J]. EMBO Rep, 2012, 13 (10): 930- 938.
doi: 10.1038/embor.2012.125
22 Bellail AC , Olson JJ , Hao C . SUMO1 modification stabilizes CDK6 protein and drives the cell cycle and glioblastoma progression[J]. Nature Commun, 2014, 5: 4234.
doi: 10.1038/ncomms5234
23 Yang W , Wang L , Roehn G , et al. Small ubiquitin-like modifier 1-3 conjugation[corrected] is activated in human astrocytic brain tumors and is required for glioblastoma cell survival[J]. Cancer Sci, 2013, 104 (1): 70- 77.
doi: 10.1111/cas.12047
24 Li H , Niu H , Peng Y , et al. Ubc9 promotes invasion and metastasis of lung cancer cells[J]. Oncol Rep, 2013, 29 (4): 1588- 1594.
doi: 10.3892/or.2013.2268
25 Shao DF , Wang XH , Li ZY , et al. High-level SAE2 promotes malignant phenotype and predicts outcome in gastric cancer[J]. Am J Cancer Res, 2015, 5 (2): 140- 154.
26 Zhang H , Kuai X , Ji Z , et al. Over-expression of small ubiquitin-related modifier-1 and sumoylated p53 in colon cancer[J]. Cell Biochem Biophys, 2013, 67 (3): 1081- 1087.
doi: 10.1007/s12013-013-9612-x
27 Guo WH , Yuan LH , Xiao ZH , et al. Overexpression of SUMO-1 in hepatocellular carcinoma: a latent target for diagnosis and therapy of hepatoma[J]. J Cancer Res Clin Oncol, 2011, 137 (3): 533- 541.
doi: 10.1007/s00432-010-0920-x
28 Chien W , Lee KL , Ding LW , et al. PIAS4 is an activator of hypoxia signaling via VHL suppression during growth of pancreatic cancer cells[J]. Br J Cancer, 2013, 109 (7): 1795- 1804.
doi: 10.1038/bjc.2013.531
29 Sternsdorf T , Jensen K , Will H . Evidence for covalent modification of the nuclear dot-associated proteins PML and Sp100 by PIC1/SUMO-1[J]. J Cell Biol, 1997, 139 (7): 1621- 1634.
doi: 10.1083/jcb.139.7.1621
30 Zhong S , Muller S , Ronchetti S , et al. Role of SUMO-1-modified PML in nuclear body formation[J]. Blood, 2000, 95 (9): 2748- 2752.
doi: 10.1182/blood.V95.9.2748.009k31a_2748_2752
31 Altmannova V , Kolesar P , Krejci L . SUMO wrestles with recombination[J]. Biomolecules, 2012, 2 (3): 350- 375.
doi: 10.3390/biom2030350
32 Bonne-Andrea C , Kahli M , Mechali F , et al. SUMO2/3 modification of cyclin E contributes to the control of replication origin firing[J]. Nat Commun, 2013, 4: 1850.
doi: 10.1038/ncomms2875
33 Carter S , Bischof O , Dejean A , et al. C-terminal modifications regulate MDM2 dissociation and nuclear export of p53[J]. Nat Cell Biol, 2007, 9 (4): 428- 435.
doi: 10.1038/ncb1562
34 Renner F , Moreno R , Schmitz ML . SUMOylation-dependent localization of IKKepsilon in PML nuclear bodies is essential for protection against DNA-damage-triggered cell death[J]. Mol Cell, 2010, 37 (4): 503- 515.
doi: 10.1016/j.molcel.2010.01.018
35 Potts PR , Yu H . The SMC5/6 complex maintains telomere length in ALT cancer cells through SUMOylation of telomere-binding proteins[J]. Nat Struct Mol Biol, 2007, 14 (7): 581- 590.
doi: 10.1038/nsmb1259
36 Li J , Xu Y , Long XD , et al. Cbx4 governs HIF-1alpha to potentiate angiogenesis of hepatocellular carcinoma by its SUMO E3 ligase activity[J]. Cancer Cell, 2014, 25 (1): 118- 131.
doi: 10.1016/j.ccr.2013.12.008
37 Cashman R , Cohen H , Ben-Hamo R , et al. SENP5 mediates breast cancer invasion via a TGFbetaRI SUMOylation cascade[J]. Oncotarget, 2014, 5 (4): 1071- 1082.
doi: 10.18632/oncotarget.1783
38 Mao H , Lebrun DG , Yang J , et al. Deregulated signaling pathways in glioblastoma multiforme: Molecular mechanisms and therapeutic targets[J]. Cancer Invest, 2012, 30 (1): 48- 56.
doi: 10.3109/07357907.2011.630050
39 Soares IN , Caetano FA , Pinder J , et al. Regulation of stress-inducible phosphoprotein 1 nuclear retention by protein inhibitor of activated STAT PIAS1[J]. Mol Cell Proteomics, 2013, 12 (11): 3253- 3270.
doi: 10.1074/mcp.M113.031005
40 Nakayama KI , Nakayama K . Ubiquitin ligases: Cell-cycle control and cancer[J]. Nat Rev Cancer, 2006, 6 (5): 369- 381.
doi: 10.1038/nrc1881
41 Bernstock JD , Ye D , Gessler FA , et al. Topotecan is a potent inhibitor of SUMOylation in glioblastoma multiforme and alters both cellular replication and metabolic programming[J]. Sci Rep, 2017, 7 (1): 7425.
42 Xu H , Rahimpour S , Nesvick CL , et al. Activation of hypoxia signaling induces phenotypic transformation of glioma cells: Implications for bevacizumab antiangiogenic therapy[J]. Oncotarget, 2015, 6 (14): 11882- 11893.
doi: 10.18632/oncotarget.3592
43 Yang Y , Xia Z , Wang X , et al. Small-molecule inhibitors targeting protein sumoylation as novel anticancer compounds[J]. Mol Pharmcol, 2018, 94 (2): 885- 894.
doi: 10.1124/mol.118.112300
44 Chen Y , Wen D , Huang Z , et al. 2-(4-Chlorophenyl)-2-oxoethyl 4-benzamidobenzoate derivatives, a novel class of SENP1 inhibitors: virtual screening, synthesis and biological evaluation[J]. Bioorg Med Chem Lett, 2012, 22 (22): 6867- 6870.
doi: 10.1016/j.bmcl.2012.09.037
45 Brave M , Dagher R , Farrell A , et al. Topotecan in combination with cisplatin for the treatment of stage IVB, recurrent, or persistent cervical cancer[J]. J Oncol, 2006, 20 (11): 1401- 1404.
46 Pommier Y . Topoisomerase I inhibitors: camptothecins and beyond[J]. J Nat Rev Cancer, 2006, 6 (10): 789.
doi: 10.1038/nrc1977
47 Ling YH , Donato NJ , Perez-Soler R . Sensitivity to topoisomerase I inhibitors and cisplatin is associated with epidermal growth factor receptor expression in human cervical squamous carcinoma ME180 sublines[J]. Cancer Chemother Pharmacol, 2001, 47 (6): 473- 480.
doi: 10.1007/s002800000239
48 Hirohama M , Kumar A , Fukuda I , et al. Spectomycin B1 as a novel SUMOylation inhibitor that directly binds to SUMO E2[J]. ACS Chem Biol, 2013, 8 (12): 2635- 2642.
doi: 10.1021/cb400630z
49 Schneekloth JS Jr . Drug discovery: controlling protein SUMOylation[J]. Nat Chem Biol, 2017, 13 (11): 1141.
doi: 10.1038/nchembio.2496
50 Fukuda I , Ito A , Hirai G , et al. Ginkgolic acid inhibits protein SUMOylation by blocking formation of the E1-SUMO intermediate[J]. Chem Biol, 2009, 16 (2): 133- 140.
doi: 10.1016/j.chembiol.2009.01.009
51 Fukuda I , Ito A , Uramoto M , et al. Kerriamycin B inhibits protein SUMOylation[J]. J Antibiot, 2009, 62 (4): 221.
doi: 10.1038/ja.2009.10
52 Takemoto M , Kawamura Y , Hirohama M , et al. Inhibition of protein SUMOylation by davidiin, an ellagitannin from Davidia involucrata[J]. J Antibiot, 2014, 67 (4): 335.
doi: 10.1038/ja.2013.142
53 Suzawa M , Miranda DA , Ramos KA , et al. A gene-expression screen identifies a non-toxic sumoylation inhibitor that mimics SUMO-less human LRH-1 in liver[J]. Elife, 2015, 4: e09003.
doi: 10.7554/eLife.09003
54 Zhao B , Villhauer EB , Bhuripanyo K , et al. SUMO-mimicking peptides inhibiting protein SUMOylation[J]. Chembiochem, 2014, 15 (18): 2662- 2666.
doi: 10.1002/cbic.201402472
55 Wu J , Lei H , Zhang J , et al. Momordin Ic, a new natural SENP1 inhibitor, inhibits prostate cancer cell proliferation[J]. Oncotarget, 2016, 7 (37): 58995- 59005.
doi: 10.18632/oncotarget.10636
56 Bernstock JD , Lee Y , Peruzzotti-Jametti L , et al. A novel quantitative high-throughput screen identifies drugs that both activate SUMO conjugation via the inhibition of microRNAs 182 and 183 and facilitate neuroprotection in a model of oxygen and glucose deprivation[J]. J Cereb Blood Flow Metab, 2016, 36 (2): 426- 441.
doi: 10.1177/0271678X15609939
57 Huang W , He T , Chai C , et al. Triptolide inhibits the proliferation of prostate cancer cells and down-regulates SUMO-specific protease 1 expression[J]. PLoS One, 2012, 7 (5): e37693.
doi: 10.1371/journal.pone.0037693
[1] 江涛. 类脑智能在脑科学的前沿应用[J]. 山东大学学报 (医学版), 2020, 58(8): 10-13.
[2] 李刚,薛皓,邱伟,赵荣荣. 脑胶质瘤抑制性免疫微环境形成机制及研究进展[J]. 山东大学学报 (医学版), 2020, 58(8): 67-73.
[3] 吴强,何泽鲲,刘琚,崔晓萌,孙双,石伟. 基于机器学习的脑胶质瘤多模态影像分析[J]. 山东大学学报 (医学版), 2020, 58(8): 81-87.
[4] 焉传祝,王伟,纪坤乾,赵玉英. 线粒体与脑疾病[J]. 山东大学学报 (医学版), 2020, 58(8): 34-41.
[5] 徐继禧,陈伟健. 髓内弥漫性中线胶质瘤伴H3 K27M突变1例[J]. 山东大学学报 (医学版), 2020, 58(7): 96-101.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
[1] 索东阳,申飞,郭皓,刘力畅,杨惠敏,杨向东. Tim-3在药物性急性肾损伤动物模型中的表达及作用机制[J]. 山东大学学报 (医学版), 2020, 58(7): 1 -6 .
[2] 张宝文,雷香丽,李瑾娜,罗湘俊,邹容. miR-21-5p靶向调控TIMP3抑制2型糖尿病肾病小鼠肾脏系膜细胞增殖及细胞外基质堆积[J]. 山东大学学报 (医学版), 2020, 58(7): 7 -14 .
[3] 龙婷婷,谢明,周璐,朱俊德. Noggin蛋白对小鼠脑缺血再灌注损伤后学习和记忆能力与齿状回结构的影响[J]. 山东大学学报 (医学版), 2020, 58(7): 15 -23 .
[4] 付洁琦,张曼,张晓璐,李卉,陈红. Toll样受体4抑制过氧化物酶体增殖物激活受体γ加重血脂蓄积的分子机制[J]. 山东大学学报 (医学版), 2020, 58(7): 24 -31 .
[5] 马青源,蒲沛东,韩飞,王超,朱洲均,王维山,史晨辉. miR-27b-3p调控SMAD1对骨肉瘤细胞增殖、迁移和侵袭作用的影响[J]. 山东大学学报 (医学版), 2020, 58(7): 32 -37 .
[6] 李宁,李娟,谢艳,李培龙,王允山,杜鲁涛,王传新. 长链非编码RNA AL109955.1在80例结直肠癌组织中的表达及对细胞增殖与迁移侵袭的影响[J]. 山东大学学报 (医学版), 2020, 58(7): 38 -46 .
[7] 史爽,李娟,米琦,王允山,杜鲁涛,王传新. 胃癌miRNAs预后风险评分模型的构建与应用[J]. 山东大学学报 (医学版), 2020, 58(7): 47 -52 .
[8] 肖娟,肖强,丛伟,李婷,丁守銮,张媛,邵纯纯,吴梅,刘佳宁,贾红英. 两种甲状腺超声数据报告系统诊断效能的比较[J]. 山东大学学报 (医学版), 2020, 58(7): 53 -59 .
[9] 丁祥云,于清梅,张文芳,庄园,郝晶. 胰岛素样生长因子II在84例多囊卵巢综合征患者颗粒细胞中的表达和促排卵结局的相关性[J]. 山东大学学报 (医学版), 2020, 58(7): 60 -66 .
[10] 徐玉香,刘煜东,张蓬,段瑞生. 101例脑小血管病患者脑微出血危险因素的回顾性分析[J]. 山东大学学报 (医学版), 2020, 58(7): 67 -71 .
版权所有 © 2018 《山东大学学报(医学版)》编辑部　
地址:山东大学科技期刊社（济南市历城区山大南路27号山东大学中心校区明德楼B座721室） 电话: 0531-88366918 E-mail: xbyxb@sdu.edu.cn
本系统由北京玛格泰克科技发展有限公司设计开发