2. Academic Validation
  3. Disulfiram impairs USP21-mediated MOF-K257 deubiquitination to inhibit esophageal squamous cell carcinoma progression

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

  • Cancer Lett. 2024 Dec 25:611:217419. doi: 10.1016/j.canlet.2024.217419.
Lingxiao Yang 1,  Huacong Sui 1,  Yi Ding 1,  Yilin Zhu 1,  Xiangqing Song 1,  Yifan Zhang 2,  Guangyan Fan 2,  Jiaxu Wang 1,  Xiujie Cui 2,  Yunfeng Jiang 3,  Shuyong Zhao 4,  Yilang Hong 4,  Ning Mu 5,  Zhongxian Tian 5,  Yunpeng Zhao 1,  Peichao Li 6,  Xiaogang Zhao 7
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 2 Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 3 Department of Thoracic Surgery, Yan Tai Yu Huang Ding Hospital, Yantai, China.
  • 4 Qilu Pharmaceutical Co., Ltd., Jinan, China.
  • 5 Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China; Key Laboratory of Precision Diagnosis and Treatment of Lung Tumors in Shandong Provincial Medicine and Health, Shandong University, Jinan, China; Key Laboratory of Basic Research and Clinical Transformation of Thoracic Tumors in Shandong Provincial Colleges and Universities, Shandong University, Jinan, China.
  • 6 Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China; Key Laboratory of Precision Diagnosis and Treatment of Lung Tumors in Shandong Provincial Medicine and Health, Shandong University, Jinan, China; Key Laboratory of Basic Research and Clinical Transformation of Thoracic Tumors in Shandong Provincial Colleges and Universities, Shandong University, Jinan, China. Electronic address: lipeichao@email.sdu.edu.cn.
  • 7 Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China; Key Laboratory of Precision Diagnosis and Treatment of Lung Tumors in Shandong Provincial Medicine and Health, Shandong University, Jinan, China; Key Laboratory of Basic Research and Clinical Transformation of Thoracic Tumors in Shandong Provincial Colleges and Universities, Shandong University, Jinan, China. Electronic address: zhaoxiaogang@sdu.edu.cn.
PMID: 39725149 DOI: 10.1016/j.canlet.2024.217419
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.

Keywords

Deubiquitination; Disulfiram; ESCC; MOF; USP21.

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