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In the present study, we investigated the molecular mechanisms underlying the melatonin\u2010mediated Bim upregulation through post\u2010translational regulation. We found that ovarian tumor domain\u2010containing protein 1 (OTUD1), a deubiquitinase belonging to the OTU protein family, is upregulated by melatonin at the mRNA and protein levels. OTUD1\u00a0knockdown inhibited melatonin\u2010induced Bim upregulation and apoptosis in cancer cells. OTUD1 directly interacted with Bim and inhibited its ubiquitination. Melatonin\u2010induced OTUD1 upregulation caused deubiquitination at the lysine 3 residue of Bim, resulting in its stabilization. In addition, melatonin\u2010induced activation of Sp1 was found to be involved in OTUD1 upregulation at the transcriptional level, and pharmacological inhibition and genetic ablation of Sp1 (siRNA) interrupted melatonin\u2010induced OTUD1\u2010mediated Bim upregulation. Furthermore, melatonin reduced tumor growth and induced upregulation of OTUD1 and Bim in a mouse xenograft model. Notably, Bim expression levels correlated with OTUD1\u00a0levels in patients with renal clear cell carcinoma. Thus, our results demonstrated that melatonin induces apoptosis by stabilizing Bim via Sp1\u2010mediated OTUD1 upregulation.<\/jats:p>","DOI":"10.1111\/jpi.12781","type":"journal-article","created":{"date-parts":[[2021,11,26]],"date-time":"2021-11-26T15:55:21Z","timestamp":1637942121000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Melatonin induces apoptotic cell death through Bim stabilization by Sp1\u2010mediated OTUD1 upregulation"],"prefix":"10.1111","volume":"72","author":[{"given":"Seon Min","family":"Woo","sequence":"first","affiliation":[{"name":"Department of Immunology, School of Medicine Keimyung University Daegu South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Un","family":"Seo","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine Keimyung University Daegu South 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