Oncogene ( IF 6.9 ) Pub Date : 2024-05-14 , DOI: 10.1038/s41388-024-03050-z
Jiahang Song 1 , Junfeng Zhang 2 , Yujing Shi 3 , Qing Gao 1 , Hui Chen 1 , Xiaofeng Ding 1 , Minghui Zhao 1 , Caiqiang Zhu 3 , Liang Liang 3 , Xinchen Sun 1 , Yingyin Zhu 4 , Wei Wang 5 , Qing Li 6 , Xiaoke Di 1
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Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy of the digestive system. Hypoxia is a crucial player in tumor ferroptosis resistance. However, the molecular mechanism of hypoxia-mediated ferroptosis resistance in ESCC remains unclear. Here, USP2 expression was decreased in ESCC cell lines subjected to hypoxia treatment and was lowly expressed in clinical ESCC specimens. Ubiquitin-specific protease 2 (USP2) depletion facilitated cell growth, which was blocked in USP2-overexpressing cells. Moreover, USP2 silencing enhanced the iron ion concentration and lipid peroxidation accumulation as well as suppressed ferroptosis, while upregulating USP2 promoted ferroptotic cell death in ESCC cells. Furthermore, knockout of USP2 in ESCC models discloses the essential role of USP2 in promoting ESCC tumorigenesis and inhibiting ferroptosis. In contrast, overexpression of USP2 contributes to antitumor effect and ferroptosis events in vivo. Specifically, USP2 stably bound to and suppressed the degradation of nuclear receptor coactivator 4 (NCOA4) by eliminating the Lys48-linked chain, which in turn triggered ferritinophagy and ferroptosis in ESCC cells. Our findings suggest that USP2 plays a crucial role in iron metabolism and ferroptosis and that the USP2/NCOA4 axis is a promising therapeutic target for the management of ESCC.
中文翻译:
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缺氧通过 USP2-NCOA4 轴抑制食管鳞状细胞癌中铁蛋白自噬介导的铁死亡
食管鳞状细胞癌(ESCC)是消化系统常见的恶性肿瘤。缺氧是肿瘤铁死亡抵抗的关键因素。然而,ESCC中缺氧介导的铁死亡抵抗的分子机制仍不清楚。在此,USP2 表达在接受缺氧处理的 ESCC 细胞系中降低,并且在临床 ESCC 标本中低表达。泛素特异性蛋白酶 2 (USP2) 消耗促进细胞生长,但在 USP2 过表达细胞中,这种生长受到抑制。此外,USP2沉默增强了铁离子浓度和脂质过氧化积累,并抑制了铁死亡,而上调USP2则促进了ESCC细胞的铁死亡。此外,ESCC模型中USP2的敲除揭示了USP2在促进ESCC肿瘤发生和抑制铁死亡中的重要作用。相反,USP2 的过度表达有助于体内抗肿瘤作用和铁死亡事件。具体来说,USP2 通过消除 Lys48 连接链稳定地结合核受体辅激活剂 4 (NCOA4) 并抑制其降解,进而引发 ESCC 细胞中的铁蛋白自噬和铁死亡。我们的研究结果表明,USP2 在铁代谢和铁死亡中发挥着至关重要的作用,并且 USP2/NCOA4 轴是食管鳞癌治疗的一个有前途的治疗靶点。