Disulfiram impairs USP21-mediated MOF-K257 deubiquitination to inhibit esophageal squamous cell carcinoma progression

IF 9.1 1区 医学 Q1 ONCOLOGY
Lingxiao Yang , Huacong Sui , Yi Ding , Yilin Zhu , Xiangqing Song , Yifan Zhang , Guangyan Fan , Jiaxu Wang , Xiujie Cui , Yunfeng Jiang , Shuyong Zhao , Yilang Hong , Ning Mu , Zhongxian Tian , Yunpeng Zhao , Peichao Li , Xiaogang Zhao
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Abstract

Disulfiram (DSF), primarily applied in the therapy for alcohol addiction, has been demonstrated to possess the promising capability of anti-tumor in many human cancers, including esophageal squamous cell carcinoma (ESCC). To date, almost all studies about DSF in ESCC are focusing on investigating either drug combinations or nanoparticle-based delivery systems. However, the exact molecular mechanisms mediating the response to DSF in ESCC are totally unknown. An increasing number of studies reported that aberrant expression of acetylation-related genes is closely involved in regulating the response of cancer cells to anti-tumor drugs. Here, we defined DSF-sensitive and -resistant cells by measuring the half-maximal inhibitory concentration (IC50) of DSF in four ESCC cell lines, followed by detecting the protein expression of nine dysregulated histone acetyltransferase (HAT) genes in ESCC. Our results demonstrate that MOF is responsible for the sensitivity to DSF in ESCC cells. Consistently, DSF treatment markedly abolished MOF-driving ESCC progression and Wnt/β-Catenin signaling activation. Interestingly, DSF decreased MOF protein expression via the ubiquitin-proteasome system. Further exploration verified the essential role of USP21, among three candidates (USP2, USP21, and USP10), in DSF-mediated MOF protein levels. Mechanistically, USP21 binds to MOF protein and decreases the ubiquitination of its K257 site, while DSF notably impedes MOF-mediated ESCC malignant progression and Wnt/β-Catenin signaling activation by blocking USP21-governed MOF-K257 deubiquitination. In conclusion, our study elucidates the USP21/MOF-K257 axis regulating the response to DSF in ESCC, which provides novel and key evidence for the clinical application of DSF in individualized therapy for ESCC patients.
双硫仑损害usp21介导的MOF-K257去泛素化以抑制食管鳞状细胞癌的进展。
双硫仑(DSF)主要用于治疗酒精成瘾,已被证明在许多人类癌症中具有良好的抗肿瘤能力,包括食管鳞状细胞癌(ESCC)。迄今为止,几乎所有关于ESCC中DSF的研究都集中在研究药物组合或基于纳米颗粒的递送系统上。然而,介导ESCC对DSF反应的确切分子机制尚不清楚。越来越多的研究报道乙酰化相关基因的异常表达与调节癌细胞对抗肿瘤药物的反应密切相关。在这里,我们通过测定4种ESCC细胞系中DSF的半最大抑制浓度(IC50)来定义DSF敏感和耐药细胞,然后检测ESCC中9个失调的组蛋白乙酰转移酶(HAT)基因的蛋白表达。我们的研究结果表明,MOF是ESCC细胞对DSF敏感的原因。与此一致,DSF治疗显著消除mof驱动的ESCC进展和Wnt/β-Catenin信号激活。有趣的是,DSF通过泛素-蛋白酶体系统降低MOF蛋白的表达。进一步的研究证实,在三个候选基因(USP2、USP21和USP10)中,USP21在dsf介导的MOF蛋白水平中发挥着重要作用。在机制上,USP21结合MOF蛋白并降低其K257位点的泛素化,而DSF通过阻断USP21调控的MOF-K257去泛素化,显著阻碍MOF介导的ESCC恶性进展和Wnt/β-Catenin信号通路激活。总之,我们的研究阐明了USP21/MOF-K257轴调控ESCC对DSF的反应,为DSF在ESCC患者个体化治疗中的临床应用提供了新的关键证据。
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来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
期刊介绍: Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.
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