SUMO化通路及其抑制剂研究概述
Overview of the Sumo-Chemical Pathway and Its Inhibitors

DOI: 10.12677/BP.2022.121003, PP. 20-25

Keywords: SUMO，SUMO化，蛋白修饰，抑制剂，癌症
SUMO, SUMOylation, Protein Modification, Inhibitor, Cancer

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Abstract:

SUMO化(SUMOylation)是一种可逆的翻译后修饰，是一种重要的分子调控机制，参与调控DNA损伤修复、免疫反应、癌变、细胞周期进程和细胞凋亡。现在已经发现了四种SUMO亚型，分别是SUMO1、SUMO2/3和SUMO4。小泛素样修饰物(SUMO)通路在所有真核生物中都是保守的，在基因表达调控、细胞信号转导和基因组完整性的维持中起着关键作用。SUMO的催化循环包括成熟、活化、偶联、连接和去修饰。SUMO系统的失调与许多疾病有关，特别是癌症。SUMO化修饰广泛参与肿瘤的癌变、DNA损伤反应、癌细胞的增殖、转移和凋亡。SUMO可以作为癌症的潜在治疗靶点。为了更好地理解SUMO在人类疾病中的作用，我们简要概述了SUMO系统的基本概念，并总结了SUMO蛋白在癌细胞中的作用以及最近关于这一通路的抑制剂研究进展。
SUMOylation, a reversible modification after translation, is a kind of molecular regulation mechanism which participated in the regulation of DNA damage repair, immune reaction, process of cancerous cell cycle and cell apoptosis. Four subtypes of SUMO have been found, including SUMO1 SUMO2/3 and SUMO4. The small ubiquitin like modification (SUMO) pathway is conserved in all eukaryotes and plays a key role in gene expression regulation of cellular signal transduction and maintenance of genomic integrity. Dysregulation of the SUMO catalytic cycle has been associated with many diseases, especially cancer. In order to better understand the role of SUMO in human disease, we briefly outline the basic concepts of the SUMO system and summarize the role of SUMO proteins in cancer cells and the advances in inhibitors of this pathway.

References

[1]	Bettermann, K., Benesch, M., Weis, S. and Haybaeck, J. (2012) SUMOylation in Carcinogenesis. Cancer Letters, 316, 113-125.
[2]	Eifler, K. and Vertegaal, A.C.O. (2015) SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer. Trends in Biochemical Sciences, 40, 779-793. https://doi.org/10.1016/j.tibs.2015.09.006
[3]	Flotho, A. and Melchior, F. (2013) SUMOylation: A Regulatory Protein Modification in Health and Disease. Annual Review of Biochemistry, 82, 357-385. https://doi.org/10.1146/annurev-biochem-061909-093311
[4]	Rabellino, A., Andreani, C. and Scaglioni, P.P. (2017) The Role of PIAS SUMO E3-Ligases in Cancer. Cancer Research, 77, 1542-1547. https://doi.org/10.1158/0008-5472.CAN-16-2958
[5]	Seeler, J.S. and Dejean, A. (2017) SUMO and the Ro-bustness of Cancer. Nature Reviews Cancer, 17, 184-197. https://doi.org/10.1038/nrc.2016.143
[6]	Wang, Y. and Dasso, M. (2009) SUMOylation and deSUMOylation at a Glance. Journal of Cell Science, 122, 4249-1252. https://doi.org/10.1242/jcs.050542
[7]	Mahajan, R., Delphin, C., Guan, T., Gerace, L. and Melchior, F. (1997) A Small Ubiquitin-Related Polypeptide Involved in Targeting RanGAP1 to Nuclear Pore Complex Protein RanBP2. Cell, 88, 97-107. https://doi.org/10.1016/S0092-8674(00)81862-0
[8]	Matunis, M.J., Coutavas, E. and Blobel, G. (1996) A Novel Ubiquitin-Like Modification Modulates the Partitioning of the Ran-GTPase-Activating Protein RanGAP1 between the Cytosol and the Nuclear Pore Complex. Journal of Cell Biology, 135, 1457-1470. https://doi.org/10.1083/jcb.135.6.1457
[9]	Saitoh, H. and Hinchey, J. (2000) Functional Heterogeneity of Small Ubiquitin-Related Protein Modifiers SUMO-1 versus SUMO-2/3. Journal of Biological Chemistry, 275, 6252-6258. https://doi.org/10.1074/jbc.275.9.6252
[10]	Nayak, A. and Müller, S. (2014) SUMO-Specific Proteas-es/Isopeptidases: SENPs and beyond. Genome Biology, 15, Article No. 422. https://doi.org/10.1186/s13059-014-0422-2
[11]	Desterro, J.M., Rodriguez, M.S., Kemp, G.D. and Hay, R.T. (1999) Identification of the Enzyme Required for Activation of the Small Ubiquitin-Like Protein SUMO-1. Journal of Biological Chemistry, 274, 10618-10624. https://doi.org/10.1074/jbc.274.15.10618
[12]	Tatham, M.H., Kim, S., Jaffray, E., Song, J., Chen, Y. and Hay, R.T. (2005) Unique Binding Interactions among Ubc9, SUMO and RanBP2 Reveal a Mechanism for SUMO Paralog Selection. Nature Structural & Molecular Biology, 12, 67-74. https://doi.org/10.1038/nsmb878
[13]	Ber-nier-Villamor, V., Sampson, D.A., Matunis, M.J. and Lima, C.D. (2002) Structural Basis for E2-Mediated SUMO Con-jugation Revealed by a Complex between Ubiquitin-Conjugating Enzyme Ubc9 and RanGAP1. Cell, 108, 345-356. https://doi.org/10.1016/S0092-8674(02)00630-X
[14]	Werner, A., Flotho, A. and Melchior, F. (2012) The RanBP2/RanGAP1*SUMO1/Ubc9 Complex Is a Multisubunit SUMO E3 Ligase. Molecular Cell, 46, 287-298. https://doi.org/10.1016/j.molcel.2012.02.017
[15]	Jackson, S.P. and Durocher, D. (2013) Regulation of DNA Damage Responses by Ubiquitin and SUMO. Molecular Cell, 49, 795-807. https://doi.org/10.1016/j.molcel.2013.01.017
[16]	Sarangi, P. and Zhao, X. (2015) SUMO-Mediated Regulation of DNA Damage Repair and Responses. Trends in Biochemical Sciences, 40, 233-242. https://doi.org/10.1016/j.tibs.2015.02.006
[17]	Moschos, S.J., Jukic, D.M., Athanassiou, C., Bhargava, R., Dacic, S., Wang, X., Kuan, S.F., Fayewicz, S.L., Galambos, C., Acquafondata, M., Dhir, R. and Becker, D. (2010) Expression Analysis of Ubc9, the Single small Ubiquitin-Like Modifier (SUMO) E2 Conjugating Enzyme, in Normal And Malig-nant Tissues. Human Pathology, 41, 1286-1298. https://doi.org/10.1016/j.humpath.2010.02.007
[18]	Zhu, S., Sachdeva, M., Wu, F., Lu, Z. and Mo, Y.Y. (2010) Ubc9 Promotes Breast Cell Invasion and Metastasis in a SUMOylation-Independent Manner. Oncogene, 29, 1763-1772. https://doi.org/10.1038/onc.2009.459
[19]	He, X., Riceberg, J., Pulukuri, S.M., Grossman, S., Shinde, V., Shah, P., Brownell, J.E., Dick, L., Newcomb, J. and Bence, N. (2015) Characterization of the Loss of SUMO Pathway Func-tion on Cancer Cells and Tumor Proliferation. PLoS ONE, 10, e0123882. https://doi.org/10.1371/journal.pone.0123882
[20]	Kessler, J.D., Kahle, K.T., Sun, T., Meerbrey, K.L., Schlabach, M.R., Schmitt, E.M., Skinner, S.O., Xu, Q., Li, M.Z., Hartman, Z.C., Rao, M., Yu, P., Dominguez-Vidana, R., Liang, A.C., Solimini, N.L., Bernardi, R.J., Yu, B., Hsu, T., Golding, I., Luo, J., Osborne, C.K., Creighton, C.J., Hilsenbeck, S.G., Schiff, R., Shaw, C.A., Elledge, S.J. and Westbrook, T.F. (2012) A SUMOylation-Dependent Transcriptional Subprogram Is Required for Myc-Driven Tumorigenesis. Science, 335, 348-353. https://doi.org/10.1126/science.1212728
[21]	Sabò, A., Doni, M. and Amati, B. (2014) SUMOylation of Myc-Family Proteins. PLoS ONE, 9, e91072. https://doi.org/10.1371/journal.pone.0091072
[22]	Evan, G. (2012) Cancer. Taking a Back Door to Target Myc. Science, 335, 293-294. https://doi.org/10.1126/science.1217819
[23]	Schimmel, J., Eifler, K., Siguresson, J.O., Cuijpers, S.A., Hendriks, I.A., Verlaan-de Vries, M., Kelstrup, C.D., Francavilla, C., Medema, R.H., Olsen, J.V. and Vertegaal, A.C. (2014) Un-covering SUMOylation Dynamicsduring Cell-Cycle Progression Reveals FoxM1 as a Key Mitotic SUMO Target Protein. Molecular Cell, 53, 1053-1066. https://doi.org/10.1016/j.molcel.2014.02.001
[24]	Wierstra, I. (2013) FOXM1 (Forkhead Box M1) in Tumorigen-esis: Overexpression in Human Cancer, Implication in Tumorigenesis, Oncogenic Functions, Tumor-Suppressive Prop-erties, and Target of Anticancer Therapy. Advances in Cancer Research, 119, 191-419. https://doi.org/10.1016/B978-0-12-407190-2.00016-2
[25]	Myatt, S.S., Kongsema, M., Man, C.W., Kelly, D.J., Gomes, A.R., Khongkow, P., Karunarathna, U., Zona, S., Langer, J.K., Dunsby, C.W., Coombes, R.C., French, P.M., Brosens, J.J. and Lam, E.W. (2013) SUMOylation Inhibits FOXM1 Activity and Delays Mitotic Transition. Oncogene, 33, 4316-4329. https://doi.org/10.1038/onc.2013.546
[26]	Gostissa, M., Hengstermann, A., Fogal, V., Sandy, P., Schwarz, S.E., Scheffner, M. and Del Sal, G. (1999) Activation of p53 by Conjugation to the Ubiquitin-Like Protein SUMO-1. The EMBO Journal, 18, 6462-6471.
[27]	Muller, S., Berger, M., Lehembre, F., Seeler, J.S., Haupt, Y. and Dejean, A. (2000) c-Jun and p53 Activity Is Modulated by SUMO-1 Modification. Journal of Biological Chemistry, 275, 13321-13329. https://doi.org/10.1074/jbc.275.18.13321
[28]	Comerford, K.M., Leonard, M.O., Karhausen, J., Carey, R., Colgan, S.P. and Taylor, C.T. (2003) Small Ubiquitin-Related Modifier-1 Modification Mediates Resolution of CREB-Dependent Responses to Hypoxia. Proceedings of the National Academy of Sciences of the United States of America, 100, 986-991. https://doi.org/10.1073/pnas.0337412100
[29]	Yang, Y., Xia, Z., Wang, X., Zhao, X., Sheng, Z., Ye, Y., He, G., Zhou, L., Zhu, H., Xu, N. and Liang, S. (2018) Small-Molecule Inhibitors Targeting Protein SUMOylation as Novel An-ticancer Compounds. Molecular Pharmacology, 94, 885-894.
[30]	Shanmugam, M.K., Garg, M., Makhija, P., Kumar, A.P., Sharifi-Rad, J., Zam, W. and Bishayee, A. (2021) Ginkgolic Acids Confer Potential Anticancer Effects by Target-ing Pro-Inflammatory and Oncogenic Signaling Molecules. Current Molecular Pharmacology, 14, 806-822. https://doi.org/10.2174/1874467214666210126112413
[31]	Liu, D., Li, Z., Yang, Z., Ma, J. and Mai, S. (2021) Ginkgoic Acid Impedes Gastric Cancer Cell Proliferation, Migration and EMT through Inhibiting the SUMOylation of IGF-1R. Chemico-Biological Interactions, 337, Article ID: 109394. https://doi.org/10.1016/j.cbi.2021.109394
[32]	He, X., Riceberg, J., Soucy, T., Koenig, E., Minissale, J., Gallery, M., Bernard, H., Yang, X., Liao, H., Rabino, C., Shah, P., Xega, K., Yan, Z.H., Sintchak, M., Bradley, J., Xu, H., Duffey, M., England, D., Mizutani, H., Hu, Z., Guo, J., Chau, R., Dick, L.R., Brownell, J.E., Newcomb, J., Langston, S., Lightcap, E.S., Bence, N. and Pulukuri, S.M. (2017) Probing the Roles of SUMOylation in Cancer Cell Biology by Us-ing A Selective SAE Inhibitor. Nature Chemical Biology, 13, 1164-1171. https://doi.org/10.1038/nchembio.2463
[33]	Li, Y.J., Du, L., Wang, J., Vega, R., Lee, T.D., Miao, Y., Al-dana-Masangkay, G., Samuels, E.R., Li, B., Ouyang, S.X., Colayco, S.A., Bobkova, E.V., Divlianska, D.B., Sergienko, E., Chung, T.D.Y., Fakih, M. and Chen, Y. (2019) Allosteric Inhibition of Ubiquitin-Like Modifications by a Class of Inhibitor of SUMO-Activating Enzyme. Cell Chemical Biology, 26, 278-288.E6. https://doi.org/10.1016/j.chembiol.2018.10.026
[34]	Biederst？dt, A., Hassan, Z., Schneeweis, C., Schick, M., Schneider, L., Muckenhuber, A., Hong, Y., Siegers, G., Nilsson, L., Wirth, M., Dantes, Z., Steiger, K., Schunck, K., Langston, S., Lenhof, H.P., Coluccio, A., Orben, F., Slawska, J., Scherger, A., Saur, D., Müller, S., Rad, R., Weichert, W., Nilsson, J., Reichert, M., Schneider, G. and Keller, U. (2020) SUMO Pathway Inhibition Targets an Aggressive Pancreatic Cancer Subtype. Gut, 69, 1472-1482. https://doi.org/10.1136/gutjnl-2018-317856
[35]	Langston, S.P., Grossman, S., England, D., Afroze, R., Bence, N., Bowman, D., Bump, N., Chau, R., Chuang, B.C., Claiborne, C., Cohen, L., Connolly, K., Duffey, M., Durvasula, N., Freeze, S., Gallery, M., Galvin, K., Gaulin, J., Gershman, R., Greenspan, P., Grieves, J., Guo, J., Gulavita, N., Hailu, S., He, X., Hoar, K., Hu, Y., Hu, Z., Ito, M., Kim, M.S., Lane, S.W., Lok, D., Lublinsky, A., Mallender, W., McIntyre, C., Minissale, J., Mizutani, H., Mizutani, M., Molchinova, N., Ono, K., Patil, A., Qian, M., Riceberg, J., Shindi, V., Sintchak, M.D., Song, K., Soucy, T., Wang, Y., Xu, H., Yang, X., Zawadzka, A., Zhang, J. and Pulukuri, S.M. (2021) Discovery of TAK-981, a First-in-Class Inhibitor of SUMO-Activating Enzyme for the Treatment of Cancer. Journal of Medicinal Chemistry, 64, 2501-2520. https://doi.org/10.1021/acs.jmedchem.0c01491
[36]	Khattar, M., Grossman, S., Xega, K., et al. (2019) TAK-981: A First in Class SUMO Inhibitor in Phase 1 Trials that Promotes Dendritic Cell Activation, Antigen-Presentation, and T Cell Priming. Cancer Research, 79, Article No. 3252. https://doi.org/10.1158/1538-7445.AM2019-3252
[37]	Berger, A., Ghasemi, O., Grossman, S., et al. (2019) Pharmacodynamic Evaluation of the Novel SUMOylation Inhibitor TAK-981 in a Mouse Tumor Model. Cancer Re-search, 79, Article No. 3079. https://doi.org/10.1158/1538-7445.AM2019-3079

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