Melatonin induces apoptotic cell death through Bim stabilization by Sp1-mediated OTUD1 upregulation.
J Pineal Res
; 72(1): e12781, 2022 Jan.
Article
em En
| MEDLINE
| ID: mdl-34826170
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Melatonina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Pineal Res
Assunto da revista:
ENDOCRINOLOGIA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Coréia do Sul