CST1 inhibits ferroptosis and promotes gastric cancer metastasis by regulating GPX4 protein stability via OTUB1.
CST1 inhibits ferroptosis and promotes gastric cancer metastasis by regulating GPX4 protein stability via OTUB1.
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CST1通过OTUB1调节GPX4蛋白稳定性抑制铁死亡并促进胃癌转移
DOI：
10.1038/s41388-022-02537-x
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发表时间：
2023-01
期刊：
影响因子：
8
通讯作者：
Zhou, Jin
中科院分区：
文献类型：
--
作者：
Li, Dongbao;Wang, Yuhong;Dong, Chao;Chen, Tao;Dong, Anqi;Ren, Jiayu;Li, Weikang;Shu, Gege;Yang, Jiaoyang;Shen, Wenhao;Qin, Lei;Hu, Lin;Zhou, Jin
转移是导致胃癌患者预后不良的重要因素，然而，导致这种细胞行为的分子机制仍不清楚。本研究探讨半胱氨酸蛋白酶抑制剂SN(Cystatin SN，CST1)在促进胃癌转移中的作用。我们推测CST1可能通过调节Gpx4和铁性下垂来调节胃癌的进展。全转录组测序结果显示，CST1在转移性癌中的表达显著增加，且高表达与预后不良相关。进一步证实CST1的过表达可显著促进胃癌细胞在体外的迁移和侵袭，增强胃癌在裸鼠体内的肝、肺和腹膜转移。同时，CST1高表达促进了胃癌细胞上皮-间充质转化(EMT)。从机制上讲，免疫共沉淀实验结合质谱分析证实，CST1可以与调节铁下垂的关键蛋白Gpx4相互作用。CST1通过募集OTUB1，提高Gpx4蛋白的稳定性，减少细胞内的ROS，从而减轻Gpx4泛素化修饰，从而抑制铁下垂，进而促进胃癌转移。此外，临床资料提示胃癌转移患者外周血和腹水中CST1水平显著升高；多因素COX回归模型分析显示，CST1是影响胃癌患者预后的独立危险因素。总体而言，我们的结果阐明了一条关键的途径，即高表达CST1可以保护胃癌细胞免受铁性下垂的侵袭，从而促进其进展和转移。CST1可能成为胃癌转移的新的肿瘤标志物和潜在的治疗靶点。
Metastasis is an important factor contributing to poor prognosis in patients with gastric cancer; yet, the molecular mechanism leading to this cell behavior is still not well understood. In this study, we explored the role of cysteine protease inhibitor SN (Cystatin SN, CST1) in promoting gastric cancer metastasis. We hypothesized that CST1 could regulate gastric cancer progression by regulating GPX4 and ferroptosis. Whole transcriptome sequencing suggested that the expression of CST1 was significantly increased in metastatic cancer, and high CST1 expression was correlated with a worse prognosis. Our data further confirmed that the overexpression of CST1 may significantly promote the migration and invasion of gastric cancer cells in vitro and enhance liver, lung, and peritoneal metastasis of gastric cancer in nude mice. Meanwhile, high expression of CST1 promoted the epithelial-mesenchymal transition (EMT) of gastric cancer cells. Mechanistically, a co-immunoprecipitation experiment combined with mass spectrometry analysis confirmed that CST1 could interact with GPX4, a key protein regulating ferroptosis. CST1 relieves GPX4 ubiquitination modification by recruiting OTUB1, improving GPX4 protein stability and reducing intracellular reactive oxygen species (ROS), thereby inhibiting ferroptosis and, in turn, promoting gastric cancer metastasis. Moreover, clinical data suggested that CST1 is significantly increased in peripheral blood and ascites of gastric cancer patients with metastasis; multivariate Cox regression model analysis showed that CST1 was an independent risk factor for the prognosis of gastric cancer patients. Overall, our results elucidated a critical pathway through which high CST1 expression protects gastric cancer cells from undergoing ferroptosis, thus promoting its progression and metastasis. CST1 may be used as a new oncological marker and potential therapeutic target for gastric cancer metastasis.
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