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In order to identify potential drug combinations in esophageal squamous cell carcinoma (ESCC), we screened a bioactive compound library with the disulfiram copper chelation product CuET. The Jumonji domain-containing protein 3 (JMJD3) and the ubiquitously transcribed tetratricopeptide repeat protein X-linked (UTX) inhibitor GSK J4 were identified. To further understand the molecular mechanism underlying the efficient drug combination, we applied quantitative mass spectrometry to analyze the signaling pathway perturbation after drug treatment. The data revealed that the synergistic effect of GSK J4 and CuET was due to the interaction among JMJD3 and UTX, which may play important roles in maintaining endoplasmic reticulum (ER) homeostasis in tumor cells. Interestingly, our clinical data analysis showed that high expression of JMJD3 and UTX was associated with T stage and worse prognosis of ESCC patients, further supporting the importance of the above findings. In conclusion, our findings suggest that the combination of CuET and targeting JMJD3\/UTX may be a safe, effective, and available treatment for ESCC.<\/jats:p>","DOI":"10.3390\/cancers15225347","type":"journal-article","created":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T08:08:58Z","timestamp":1699517338000},"page":"5347","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting Esophageal Squamous Cell Carcinoma by Combining Copper Ionophore Disulfiram and JMJD3\/UTX Inhibitor GSK J4"],"prefix":"10.3390","volume":"15","author":[{"given":"Canlin","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Oncology, The Affiliated Taizhou People\u2019s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou 225300, China"},{"name":"Taizhou People\u2019s Hospital Affiliated to Nanjing University of Chinese Medicine, Taizhou 225300, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Affiliated Taizhou People\u2019s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou 225300, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Affiliated Taizhou People\u2019s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou 225300, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Zhang","sequence":"additional","affiliation":[{"name":"National Research Center for Translational Medicine (Shanghai), State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Jiao","sequence":"additional","affiliation":[{"name":"National Research Center for Translational Medicine (Shanghai), State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6326-3906","authenticated-orcid":false,"given":"Jianming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3483-3337","authenticated-orcid":false,"given":"Junxing","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Affiliated Taizhou People\u2019s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou 225300, China"},{"name":"Taizhou People\u2019s Hospital Affiliated to Nanjing University of Chinese Medicine, Taizhou 225300, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1016\/S0140-6736(17)31462-9","article-title":"Oesophageal cancer","volume":"390","author":"Lagergren","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21332","article-title":"Cancer statistics, 2016","volume":"66","author":"Siegel","year":"2016","journal-title":"CA Cancer J. 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