한빛사논문
- 조회706
Seon Min Woo1, Seung Un Seo1, Kyoung-jin Min2, Taeg Kyu Kwon1,3,*
1Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, South Korea. 2New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, South Korea. 3Center for Forensic Pharmaceutical Science, Keimyung University, Daegu 42601, South Korea
Seon Min Woo and Seung Un Seo contributed equally to the present study.
*Corresponding author
Abstract
Melatonin, secreted by the pineal gland, regulates the circadian rhythms and also plays an oncostatic roles in cancer cells. Previously, we showed that melatonin induced the expression of Bim, a pro-apoptotic Bcl-2 protein, at both the transcriptional and post-translational levels. In the present study, we investigated the molecular mechanisms underlying the melatonin-mediated Bim upregulation through post-translational regulation. We found that ovarian tumor domain-containing protein 1 (OTUD1), a deubiquitinase belonging to the OTU protein family, is upregulated by melatonin at the mRNA and protein levels. OTUD1 knockdown inhibited melatonin-induced Bim upregulation and apoptosis in cancer cells. OTUD1 directly interacted with Bim and inhibited its ubiquitination. Melatonin-induced OTUD1 upregulation caused deubiquitnation at the lysine 3 residue of Bim, resulting in its stabilization. In addition, melatonin-induced 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-induced OTUD1-mediated 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 levels in patients with renal clear cell carcinoma. Thus, our results demonstrated that melatonin induced apoptosis by stabilizing Bim via Sp1-mediated OTUD1 upregulation.
논문정보
- Research article
- 2021년 11월 (BRIC 등록일 2021-12-07)
- 국내 연구진
- 생명과학 > 세포생물학
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