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Melatonin reduces proliferation and promotes apoptosis of bladder cancer cells by suppressing O‐GlcNAcylation of cyclin‐dependent‐like kinase 5
Author(s) -
Wu Jinpeng,
Tan Zengqi,
Li Hongjiao,
Lin Meixuan,
Jiang Yazhuo,
Liang Liang,
Ma Qilong,
Gou Junjie,
Ning Lulu,
Li Xiang,
Guan Feng
Publication year - 2021
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12765
Subject(s) - melatonin , apoptosis , ribosomal protein s6 , cancer cell , kinase , cell growth , biology , microbiology and biotechnology , endocrinology , chemistry , medicine , cancer research , cancer , biochemistry , protein kinase a , protein phosphorylation
Melatonin helps to maintain circadian rhythm, exerts anticancer activity, and plays key roles in regulation of glucose homeostasis and energy metabolism. Glycosylation, a form of metabolic flux from glucose or other monosaccharides, is a common post‐translational modification. Dysregulated glycosylation, particularly O‐GlcNAcylation, is often a biomarker of cancer cells. In this study, elevated O‐GlcNAc level in bladder cancer was inhibited by melatonin treatment. Melatonin treatment inhibited proliferation and migration and enhanced apoptosis of bladder cancer cells. Proteomic analysis revealed reduction in cyclin‐dependent‐like kinase 5 (CDK5) expression by melatonin. O‐GlcNAc modification determined the conformation of critical T‐loop domain on CDK5 and further influenced the CDK5 stability. The mechanism whereby melatonin suppressed O‐GlcNAc level was based on decreased glucose uptake and metabolic flux from glucose to UDP‐GlcNAc, and consequent reduction in CDK5 expression. Melatonin treatment, inhibition of O‐GlcNAcylation by OSMI‐1, or mutation of key O‐GlcNAc site strongly suppressed in vivo tumor growth. Our findings indicate that melatonin reduces proliferation and promotes apoptosis of bladder cancer cells by suppressing O‐GlcNAcylation of CDK5.