BP Bioprocess 2164-5566 Scientific Research Publishing 10.12677/BP.2022.121003 BP-49531 BP20220100000_78535473.pdf 生命科学 SUMO化通路及其抑制剂研究概述 Overview of the Sumo-Chemical Pathway and Its Inhibitors 于 祥旭 2 1 陆 美玲 2 1 中国药科大学生命科学与技术学院，江苏 南京 null 22 03 2022 12 01 20 25 © Copyright 2014 by authors and Scientific Research Publishing Inc. 2014 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

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.

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

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。

 关键词

SUMO，SUMO化，蛋白修饰，抑制剂，癌症

 Overview of the Sumo-Chemical Pathway and Its Inhibitors<sup> </sup>

Xiangxu Yu, Meiling Lu*

College of Life Science and Technology, China Pharmaceutical University, Nanjing Jiangsu

Received: Feb. 22nd, 2022; accepted: Mar. 15th, 2022; published: Mar. 22nd, 2022

 ABSTRACT

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.

Keywords:SUMO, SUMOylation, Protein Modification, Inhibitor, Cancer

Copyright © 2022 by author(s) and beplay安卓登录

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

 1. 引言

SUMO修饰作为一种广泛应用的翻译后蛋白修饰，越来越受到人们的关注。由于这一途径几乎存在于所有真核生物中，对于维持基因组的完整性、转录调控、基因表达和细胞内信号转导的调控至关重要 [ 1 ]。SUMO化调节了许多生物过程，包括DNA损伤修复、免疫反应、癌变、细胞周期进程和细胞凋亡 [ 2 ] [ 3 ]。小泛素样修饰物(SUMO)也参与了线粒体分裂、离子通道和生物节律的调节。因此，多层调控或SUMO修饰可能在复杂的蛋白调控网络中发挥重要作用。SUMO化作用的紊乱可导致某些疾病和肿瘤的发展。因此，SUMO可以作为一种潜在的癌症治疗靶点 [ 4 ] [ 5 ]。

 2. SUMO蛋白和SUMO催化循环

SUMO蛋白是是泛素样蛋白质家族的一种。然而，二者氨基序列同源性仅为18%，但两者的三维结构非常相似，包含一个典型的ββαββαβ折叠以及C端双甘油的结构 [ 6 ]。SUMO蛋白于1996年首次被发现，在哺乳动物中有三种SUMO亚型，即SUMO1、SUMO2和SUMO3 [ 7 ] [ 8 ]。SUMO2和SUMO3在氨基酸序列上非常相似，通常被写为SUMO2/3。SUMO1主要修饰生理状态蛋白，而SUMO2/3主要修饰应激蛋白 [ 9 ]。

SUMO循环和泛素循环相似，但功能不同。泛素修饰的靶蛋白主要使靶蛋白被蛋白酶体识别和降解，而SUMO修饰的蛋白更稳定，SUMOylation调节蛋白–蛋白相互作用，从而介导靶蛋白的定位和功能调控。所有的SUMO蛋白都经历了相同的酶催化机制，即底物蛋白的附着或解离。SUMO化通路：包括成熟、活化、偶联、连接和去修饰，大致步骤与同泛素样蛋白，具体如下所述：

成熟：该SUMO蛋白在体内是一个非活性的前体分子。人体中它被中心蛋白特异性蛋白酶1(SENP)切割C末端的四个氨基酸后激活 [ 10 ]。

活化：SUMO E1激活酶是一种110kDa的蛋白质，包含两个亚基，分别是SUMO激活酶E1 (SAE1或Aos1)和SUMO激活酶E2 (SAE2或Uba2)。这两个亚基通常形成SAE1-SAE2的异源二聚体。在ATP的作用下异源二聚体，通过硫酯键将其C端羧基与SAE2/Uba2的半胱氨酸残基连接起来，从而激活SUMO蛋白 [ 11 ]。

偶联：唯一一种E2 (SUMOE2或Ubc9)。活化的SUMO蛋白通过酯交换反应转移到Ubc9保守的93号半胱氨酸残基上，形成E2-SUMO硫酯化合物。最后，Ubc9通过异肽键将SUMO分子连接到目标蛋白的赖氨酸残基上，从而完成SUMO化 [ 12 ]。

连接：虽然实验表明，SUMOE1和E2可以使底物SUMO化，但E3连接酶在SUMO蛋白靶向底物 [ 13 ] 的过程中是必不可少的。SUMOE3连接酶识别底物，并通过两种不同的机制参与SUMO化的促进。SUMOE3连接酶，可以通过稳定底物和SUMOE2复合物的接触，促进SUMO蛋白与E2的解离，然后将SUMO蛋白连接到底物 [ 14 ] 上。通过对SUMOE2复合物的精确定位，SUMOE3连接酶降低了SUMOE2复合物的硫酯键与底物赖氨酸残基之间的距离，使其足够近，从而提高了底物的特异性。

 3. 肿瘤发生中的SUMO化

SUMO化是一种重要的翻译后修饰，几乎可以微调所有的细胞功能和病理进程。SUMO化在人类肿瘤发生中的重要作用已逐渐显现。SUMO信号通路中不同成分的表达或活性的改变可能会完全改变细胞的性质。SUMO通路通过调控癌变蛋白诱导细胞增殖、抗凋亡和转移潜能 [ 15 ] [ 16 ]。异常的SUMO化可导致包括癌症在内许多疾病的发展。虽然SUMO信号通路中各种成分的表达与癌症发展或转移之间的关系尚未完全了解，但越来越多的研究表明，SUMOylation在癌症中发挥着重要作用 [ 5 ]。

3.1. 肿瘤细胞中SUMO的改变

SUMO机制的组成部分在癌症组织中高表达，这表明激活的许多SUMO化修饰与肿瘤生长有关，SUMO偶联酶Ubc9的过表达发生在多种类型的癌症中，包括卵巢癌 [ 17 ]、结肠癌和前列腺癌 [ 18 ]，并促进细胞侵袭和转移 [ 19 ]。此外，许多肿瘤中会发生多种SUMO蛋白酶的过表达，包括SENP1和SENP5，这表明SUMO化进程需要严格调控，以防止肿瘤细胞恶性进展和增殖。敲除SUMO E1中的SAE2的明显抑制了小鼠结肠肿瘤的生长，表明SUMO修饰与肿瘤生长的功能相关性。同样，在myc依赖性乳腺癌患者中，低水平的SUMO激活酶显示较长的生存期 [ 20 ]。这些发现表明了利用靶向SUMO机制进行癌症治疗的潜力。

 3.2. SUMO化介导的癌基因和肿瘤抑制因子的调控

转录因子c-Myc是参与细胞增殖和凋亡的致癌基因之一。c-Myc的异常上调在肿瘤发生中十分普遍。最近研究发现SUMO修饰的c-Myc可以被蛋白酶体快速降解 [ 21 ]。此外，c-Myc特异性地SUMO化可视作蛋白质应激反应一种信号，在c-myc诱发的小鼠乳腺癌模型中，敲除SUMO激活酶，SAE2，可以阻断癌症的进展，但SUMO化修饰如何促进c-myc相关的肿瘤发生的相关机制尚不清楚。敲除SUMO连接酶PIAS1可以降低c-Myc的SUMO化水平，并导致c-Myc相关的报告基因表达增加。尽管仍有机制问题未解决，由于c-Myc诱发的肿瘤与SUMO化系统的相关性，为阻断这一致癌基因提供了新的思路 [ 22 ]。

叉头框转录因1 (FoxM1)，另一个关键的增殖转录因子，其表达也受到SUMO化的调控 [ 23 ]。FoxM1在许多类型的实体肿瘤中都会过表达，如乳腺癌、结肠癌、肺癌、前列腺癌和肝癌 [ 24 ]。而在这些研究中不同的FoxM1的SUMO化突变表现出相互矛盾的结果 [ 23 ] [ 25 ]。SUMO1修饰的FoxM1可以抑制其转录活性，导致泛素化增加，随后FoxM1降解，从而减少有丝分裂进程。而FoxM1与SUMO2的SUMO酰化可以增加其转录活性，从而促进细胞增殖 [ 25 ] 而SUMO2的SUMO酰化可以增加其转录活性 [ 23 ]，从而促进细胞增殖。

蛋白质组学研究表明，大部分SUMO酰化的蛋白质组参与了转录调控和染色质重塑。许多转录因子，如p53 [ 26 ]、c-Jun [ 27 ]、和cAMP反应元件结合蛋白CREB [ 28 ] 等致癌基因和肿瘤抑制因子，在许多肿瘤中表达下调。虽然SUMO化对这些调控因子活性的影响已被部分确定，但目前尚不清楚这些靶蛋白的SUMO化是否在人类肿瘤中减少表达。因此，从这些组织中高效地纯化SUMO靶点将是很有意义的，这是目前SUMO研究领域的一个主要挑战。

 4. SUMO酰化抑制剂

如上所述，SUMO通路中的许多蛋白在肿瘤组织中过表达，而SUMO通路中某些蛋白的敲除会阻断癌细胞增殖并诱导癌细胞凋亡。因此，开发专门阻断SUMO化机制活性的化合物十分有意义，在过去的20年里，SUMO化通路已经成为癌症治疗的有吸引力的靶点。在早期，已经鉴定出了几种SUMO-E1抑制剂，包括银杏酸、克霉素B和davidiin，以及SUMOE2 (UBC9)抑制剂2D-08、GSK145A，但这些分子缺乏特异性并且效率不高(半抑制浓度在mM范围内) [ 29 ] [ 30 ] [ 31 ]。2017年，鉴定出的ML-792可以与SUMO形成复合物，选择性地阻断SAE活性，并作为SUMOE1的竞争性抑制剂，是一种高效并有高选择性的SUMOE1抑制剂。ML-792在体外抑制癌细胞增殖，同时MYC上调的肿瘤细胞对ML-792具有更高的敏感性 [ 32 ]。接下来发现的SUMOE1酶的共价变构抑制剂COH000，其可以共价结合在远离活性位点的Cys30上，呈现出非竞争性抑制剂模式。在体外，COH000抑制癌细胞增殖，降低淋巴瘤细胞系中Myc的表达。更重要的是，在体内，COH000表现出结直肠异种移以及原发性结直肠样本抗肿瘤活性 [ 33 ]。

ML-93是ML-792的衍生物，作为SUMO通路中E1抑制剂，在胰腺导管癌(PDAC)中发现有明显的作用。ML-93抑制了PDAC-NOD异种移植小鼠模型中的肿瘤生长，并抑制了体外原发性PDO，这为通过研究SUMO通路抑制剂，进而靶向PDAC的亚型提供了证据。

靶向SUMO通路的重大突破是ML-792的另一个衍生物TAK-981，目前已经在成人患者中进行实体瘤和淋巴瘤的Ⅰ期临床测试 [ 34 ]。HCT116肿瘤细胞系中，通过免疫荧光实验监测SUMO蛋白从细胞核到细胞质的过程，发现与ML-792相比，TAK-981在细胞SUMO通路抑制中表现出类似的半数抑制浓度(10nMvs15nM)。但是TAK-981表现出更高的药效性以及更长的有效时间。

在HCT116异种移植模型中，与ML-792相比，TAK-981在更低的周剂量(50 mg/kg QDX3/周，周总剂量1/4 150 mg/kg)下表现出相同的肿瘤生长抑制，在OCI-Ly10异种移植模型中也观察到类似的肿瘤抑制效果 [ 35 ]。TAK-981显示了免疫细胞中I型IFN信号通路的上调，TAK-981被证明可以促进先天免疫应答，以及I型IFN依赖的先天免疫细胞的激活，包括巨噬细胞、NK细胞和树突状细胞，以及T细胞。在小鼠同基因肿瘤模型中，TAK-981可以促进先天免疫反应，能够引发抗肿瘤适应性免疫应答反应 [ 36 ]。

目前，TAK-981与其他抗体联用已经进入临床试验，其中包括用于治疗转移性实体肿瘤的PD1抗体派姆单抗以及用于治疗非霍奇金淋巴瘤的CD20抗体利妥昔单抗 [ 37 ]。该研究不仅推进了人类临床试验中的第一个SUMO通路中E1抑制剂，而且为抑制肿瘤进展和免疫逃避以增强癌症治疗的新策略提供了新的见解。

 5. 总结

从上述研究来看，SUMO修饰可能通过广泛的调控机制提高复杂信号通路的稳定性。对SUMO修饰在信号通路中的研究表明，SUMO蛋白通常靶向多个蛋白。SUMO修饰是一种重要的翻译后修饰，它不仅是调节细胞活性的关键因素，而且在病理过程中起着作用，这已被接受和证实。SUMO修饰与癌变和增殖密切相关，然而，其潜在的分子机制仍不清楚。SUMO化蛋白在大多数癌症中显著上调，因此可能是癌症治疗的一个潜在靶点，一些SUMO抑制剂已经被开发成功。然而，为了验证这些发现，并为癌症的诊断和预后提供有用的信息，则需要大量的临床试验。

 文章引用

于祥旭,陆美玲. SUMO化通路及其抑制剂研究概述 Overview of the Sumo-Chemical Pathway and Its Inhibitors[J]. 生物过程, 2022, 12(01): 20-25. https://doi.org/10.12677/BP.2022.121003

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