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.

中文翻译：

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褪黑激素通过抑制细胞周期蛋白依赖性激酶 5 的 O-GlcNAcylation 来减少膀胱癌细胞的增殖并促进细胞凋亡

褪黑激素有助于维持昼夜节律，发挥抗癌活性，并在调节葡萄糖稳态和能量代谢中起关键作用。糖基化是一种来自葡萄糖或其他单糖的代谢流形式，是一种常见的翻译后修饰。失调的糖基化，尤其是 O-GlcNAcylation，通常是癌细胞的生物标志物。在这项研究中，褪黑激素治疗抑制了膀胱癌中升高的 O-GlcNAc 水平。褪黑激素治疗可抑制膀胱癌细胞的增殖和迁移并增强细胞凋亡。蛋白质组学分析显示褪黑激素降低了细胞周期蛋白依赖性样激酶 5 (CDK5) 的表达。O-GlcNAc 修饰决定了 CDK5 上关键 T 环结构域的构象，并进一步影响了 CDK5 的稳定性。褪黑激素抑制 O-GlcNAc 水平的机制是基于减少葡萄糖摄取和从葡萄糖到 UDP-GlcNAc 的代谢通量，以及随之而来的 CDK5 表达减少。褪黑激素治疗、OSMI-1 抑制 O-GlcNAc 化或关键 O-GlcNAc 位点突变强烈抑制体内肿瘤生长。我们的研究结果表明，褪黑激素通过抑制 CDK5 的 O-GlcNAcylation 来减少膀胱癌细胞的增殖并促进细胞凋亡。