GSTM3 deficiency impedes DNA mismatch repair to promote gastric tumorigenesis via CAND1/NRF2-KEAP1 signaling
GSTM3 deficiency impedes DNA mismatch repair to promote gastric tumorigenesis via CAND1/NRF2-KEAP1 signaling
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DOI：
10.1016/j.canlet.2022.215692
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发表时间：
2022-04-29
期刊：
影响因子：
9.7
通讯作者：
Zhang, Yonglong
中科院分区：
文献类型：
--
作者：
Chen, Tao;Jinlin, Duan;Zhang, Yonglong
胃癌是世界范围内最严重的胃疾病之一。然而，驱动肿瘤发生和进展的分子基础尚未完全理解，这阻碍了治疗方案的有效性和发展。谷胱甘肽-S-转移酶（GST）是一组维持氧化还原稳态的II相解毒酶;然而，它们在癌症中的作用尚未明确。在这里，我们揭示了GST家族成员的表达在GC组织中显著受损。谷胱甘肽-S-转移酶mu 3（GSTM 3）是GST家族的成员，在胃癌组织中表达显著下调，在体内外实验中均能抑制胃癌细胞的增殖和迁移，是胃癌的独立预后因子，与肿瘤分化有关。从机制上讲，GSTM 3是由NRF 2/KEAP 1信号转导转录激活的。作为反馈环，GSTM 3与Cullin相关和neddylation-dissociated 1蛋白（CAND 1）结合，CAND 1是一种用于将Kelch样ECH相关蛋白1（KEAP 1）整合到Cul 3-RING泛素连接酶（CRL 3）中的交换因子，以破坏核因子-红细胞因子2相关因子2（NRF 2）/KEAP 1结合并阻止NRF 2泛素化和降解，导致其活化。谷胱甘肽S-转移酶Mu 3（GSTM 3）的缺乏会降低DNA错配修复（MMR）基因的表达，并通过CAND 1/NRF 2结合增加诱变。重要的是，GSTM 3/NRF 2和KEAP 1分别与微卫星不稳定性的基因组特征负相关和正相关。临床上，GSTM 3、NRF 2和MutS同源物6（MSH 6）在GC标本中呈正相关。本研究揭示了GSTM 3和NRF 2之间的相互调节作用，并建立了GSTM 3-NRF 2/KEAP 1与胃癌细胞增殖和进展过程中MMR的功能和临床联系，从而为胃癌的治疗提供了潜在的靶点。
Gastric cancer (GC) is one of the most severe gastric diseases worldwide. However, the molecular basis that drives tumorigenesis and progression is not completely understood, which hinders the efficacy and development of therapeutic options. Glutathione-S-transferases (GSTs) are a group of phase II detoxification enzymes that maintain redox homeostasis; however, their roles in cancers are not well defined. Here, we revealed that the expression of GST family members is significantly impaired in GC tissues. Glutathione-S-transferase mu 3 (GSTM3), a member of GST family, is dramatically downregulated in cancerous tissues and has been identified as an independent prognostic factor in GC associated with tumor differentiation, inhibiting GC cell proliferation and migration in vitro and in vivo. Mechanistically, GSTM3 is transcriptionally activated by NRF2/KEAP1 signaling. As a feedback loop, GSTM3 binds to Cullin-associated and neddylation-dissociated 1 protein (CAND1), an exchange factor for integrating Kelch-like ECH-associated protein 1 (KEAP1) into Cul3-RING ubiquitin ligases (CRL3), to disrupt nuclear factor-erythroid factor 2-related factor 2 (NRF2)/KEAP1 binding and prevent NRF2 ubiquitination and degradation, leading to its activation. A deficiency in glutathione S-Transferase Mu 3 (GSTM3) reduces DNA mismatch repair (MMR) gene expression and increases mutagenesis via CAND1/NRF2 binding. Importantly, GSTM3/NRF2 and KEAP1 were negatively and positively associated with the genomic signature for microsatellite instability, respectively. Clinically, GSTM3, NRF2, and MutS homolog 6 (MSH6) were positively correlated in the GC specimens. This study uncovered a reciprocal regulation between GSTM3 and NRF2 and established a functional and clinical link between GSTM3-NRF2/KEAP1 and MMR during GC cell proliferation and progression, thus providing potential therapeutic targets for GC.