Targeting MUS81 promotes the anticancer effect of WEE1 inhibitor and immune checkpoint blocking combination therapy via activating cGAS/STING signaling in gastric cancer cells.
Targeting MUS81 promotes the anticancer effect of WEE1 inhibitor and immune checkpoint blocking combination therapy via activating cGAS/STING signaling in gastric cancer cells.
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靶向MUS81通过激活胃癌细胞中的cGAS/STING信号传导促进WEE1抑制剂和免疫检查点阻断联合疗法的抗癌作用
DOI：
10.1186/s13046-021-02120-4
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发表时间：
2021-10-08
期刊：
影响因子：
--
通讯作者：
Tao K
中科院分区：
文献类型：
--
作者：
Li C;Shen Q;Zhang P;Wang T;Liu W;Li R;Ma X;Zeng X;Yin Y;Tao K
识别基因组生物标记物以预测特定药物的抗癌效果被认为是发展精密医学的一种有前途的策略。DNA内切酶MUS81在恶性疾病的各种生物学过程中起着关键作用，主要是在DNA损伤修复和复制叉稳定性方面。我们先前的研究报道，MUS81在胃癌中高表达，并与肿瘤转移有关；然而，其治疗价值尚未完全阐明。生物信息学分析用于确定与MUS81相关的差异基因，并在临床组织样本中进一步验证。建立MUS81细胞功能获得或丧失模型，探讨MUS81对WEE1表达的影响及其机制。此外，通过体内和体外实验验证了靶向MUS81联合WEE1抑制剂的抗肿瘤作用。然后对cGAS/STING通路进行评价，确定MUS81在胃癌免疫治疗中的治疗价值。在本研究中，MUS81与细胞周期检查点激酶WEE1的表达呈负相关。此外，我们还发现MUS81通过E-3连接酶β-TrCP以一种酶的方式调节WEE1的泛素化。此外，抑制MUS81可以增敏WEE1抑制剂MK1775在体内外对胃癌的抗癌作用。有趣的是，当MUS81被作为靶点时，它增加了MK1775诱导的胞浆DNA的积聚，并激活了DNA传感器刺痛介导的天然免疫。因此，WEE1抑制剂MK1775特异性地增强了免疫检查点阻断治疗对MUS81缺陷的胃癌细胞的抗癌作用。我们的数据为靶向MUS81可以通过调节其泛素化而上调WEE1的表达并激活天然免疫反应，从而增强WEE1抑制剂和免疫检查点阻断联合治疗对胃癌细胞的抗癌作用提供了合理的证据。网上版载有补充材料，可在10.1186/s13046-021-02120-4查阅。
Identification of genomic biomarkers to predict the anticancer effects of indicated drugs is considered a promising strategy for the development of precision medicine. DNA endonuclease MUS81 plays a pivotal role in various biological processes during malignant diseases, mainly in DNA damage repair and replication fork stability. Our previous study reported that MUS81 was highly expressed and linked to tumor metastasis in gastric cancer; however, its therapeutic value has not been fully elucidated. Bioinformatics analysis was used to define MUS81-related differential genes, which were further validated in clinical tissue samples. Gain or loss of function MUS81 cell models were constructed to elucidate the effect and mechanism of MUS81 on WEE1 expression. Moreover, the antitumor effect of targeting MUS81 combined with WEE1 inhibitors was verified using in vivo and in vitro assays. Thereafter, the cGAS/STING pathway was evaluated, and the therapeutic value of MUS81 for immunotherapy of gastric cancer was determined. In this study, MUS81 negatively correlated with the expression of cell cycle checkpoint kinase WEE1. Furthermore, we identified that MUS81 regulated the ubiquitination of WEE1 via E-3 ligase β-TRCP in an enzymatic manner. In addition, MUS81 inhibition could sensitize the anticancer effect of the WEE1 inhibitor MK1775 in gastric cancer in vitro and in vivo. Interestingly, when MUS81 was targeted, it increased the accumulation of cytosolic DNA induced by MK1775 treatment and activated the DNA sensor STING-mediated innate immunity in the gastric cancer cells. Thus, the WEE1 inhibitor MK1775 specifically enhanced the anticancer effect of immune checkpoint blockade therapy in MUS81 deficient gastric cancer cells. Our data provide rational evidence that targeting MUS81 could elevate the expression of WEE1 by regulating its ubiquitination and could activate the innate immune response, thereby enhancing the anticancer efficacy of WEE1 inhibitor and immune checkpoint blockade combination therapy in gastric cancer cells. The online version contains supplementary material available at 10.1186/s13046-021-02120-4.
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