Melatonin induces apoptotic cell death through Bim stabilization by Sp1-mediated OTUD1 upregulation
Seon Min Woo1, Seung Un Seo1, Kyoung-Jin Min2
1Department of Immunology, School of Medicine, Keimyung University, Daegu, South Korea.
Abstract:
Melatonin, secreted by the pineal gland, regulates the circadian rhythms and also plays an oncostatic role in cancer cells. Previously, we showed that melatonin induces 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 deubiquitination 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 induces apoptosis by stabilizing Bim via Sp1-mediated OTUD1 upregulation.
Insights
Melatonin stabilizes the pro-apoptotic protein Bim by upregulating ovarian tumor domain-containing protein 1 (OTUD1) via Sp1 activation. This mechanism enhances cancer cell apoptosis and reduces tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Melatonin, a pineal gland hormone, exhibits oncostatic properties.
- Melatonin influences cancer cell apoptosis through proteins like Bim.
- Previous studies indicated melatonin affects Bim expression transcriptionally and post-translationally.
Purpose of the Study:
- To elucidate the molecular mechanisms of melatonin-induced Bim upregulation via post-translational regulation.
- To investigate the role of ovarian tumor domain-containing protein 1 (OTUD1) in melatonin's oncostatic effects.
Main Methods:
- Investigated melatonin's effect on OTUD1 expression at mRNA and protein levels.
- Utilized OTUD1 knockdown and Sp1 inhibition (siRNA) to assess their impact on Bim upregulation and apoptosis.
- Performed co-immunoprecipitation to confirm OTUD1-Bim interaction and analyzed Bim ubiquitination.
- Evaluated melatonin's effect on tumor growth in a mouse xenograft model.
- Correlated OTUD1 and Bim expression in human renal clear cell carcinoma samples.
Main Results:
- Melatonin upregulates OTUD1 expression at both mRNA and protein levels.
- OTUD1 knockdown abrogates melatonin-induced Bim upregulation and cancer cell apoptosis.
- OTUD1 directly interacts with Bim, deubiquitinates it at lysine 3, leading to stabilization.
- Melatonin-induced Sp1 activation is crucial for transcriptional upregulation of OTUD1.
- Melatonin treatment reduces tumor growth in vivo and increases OTUD1 and Bim levels.
- Bim expression positively correlates with OTUD1 levels in renal clear cell carcinoma patients.
Conclusions:
- Melatonin induces cancer cell apoptosis by stabilizing Bim through Sp1-mediated OTUD1 upregulation.
- The Sp1-OTUD1-Bim axis represents a key pathway in melatonin's anti-cancer activity.
- Findings highlight OTUD1 as a potential therapeutic target in melatonin-based cancer treatments.
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