分子昼夜节律时钟用于调控健康组织中基因、蛋白质和代谢产物的24小时节律振荡。然而，在许多人类癌症中，这一节律遭到了破坏。已经发现，MYC致癌蛋白的异常表达会改变分子时钟基因的表达，并导致多种癌症类型中分子时钟节律的紊乱。目前尚不清楚癌细胞通过抑制钟摆节律获得何种益处，以及这种分子钟节律的丧失如何影响癌症中全局基因表达和代谢。我们假设MYC或其类似物N-MYC（在此统称为MYC）通过抑制基因表达和代谢的振荡，以非振荡的方式上调生物合成途径。为了验证这一假设，我们研究了具有可诱导MYC的不同癌症类型的细胞，并使用时间序列RNA测序和代谢组学来确定MYC激活对基因、基因表达途径和代谢产物的全局振荡破坏程度。我们的重点分析了在多个癌细胞系模型中共同发生变化的基因、途径和代谢产物。我们在此报道，MYC破坏了超过85％的振荡基因，并促进了核糖体和线粒体生物合成，并抑制了细胞附着途径。值得注意的是，在激活MYC时，之前具有环周性变化的生物合成程序以非振荡的方式上调。此外，MYC的激活取消了营养物质转运蛋白的振荡，并大幅上调了转运蛋白的表达、细胞表面定位和细胞内氨基酸库。最后，我们报道了MYC破坏了代谢物的振荡以及氨基酸代谢与核苷酸代谢的时间分离。我们的结果表明，MYC对分子昼夜节律时钟的破坏会使代谢和生物合成过程摆脱昼夜控制，这可能为癌细胞提供了独特的优势。版权：©2023 Cazarin等。本文为开放获取文章，根据知识共享署名许可，允许任何人在任何媒介下使用、分发和重制，只要原作者和资源来源被署名。

The molecular circadian clock, which controls rhythmic 24-hour oscillation of genes, proteins, and metabolites in healthy tissues, is disrupted across many human cancers. Deregulated expression of the MYC oncoprotein has been shown to alter expression of molecular clock genes, leading to a disruption of molecular clock oscillation across cancer types. It remains unclear what benefit cancer cells gain from suppressing clock oscillation, and how this loss of molecular clock oscillation impacts global gene expression and metabolism in cancer. We hypothesized that MYC or its paralog N-MYC (collectively termed MYC herein) suppress oscillation of gene expression and metabolism to upregulate pathways involved in biosynthesis in a static, non-oscillatory fashion. To test this, cells from distinct cancer types with inducible MYC were examined, using time-series RNA-sequencing and metabolomics, to determine the extent to which MYC activation disrupts global oscillation of genes, gene expression pathways, and metabolites. We focused our analyses on genes, pathways, and metabolites that changed in common across multiple cancer cell line models. We report here that MYC disrupted over 85% of oscillating genes, while instead promoting enhanced ribosomal and mitochondrial biogenesis and suppressed cell attachment pathways. Notably, when MYC is activated, biosynthetic programs that were formerly circadian flipped to being upregulated in an oscillation-free manner. Further, activation of MYC ablates the oscillation of nutrient transporter proteins while greatly upregulating transporter expression, cell surface localization, and intracellular amino acid pools. Finally, we report that MYC disrupts metabolite oscillations and the temporal segregation of amino acid metabolism from nucleotide metabolism. Our results demonstrate that MYC disruption of the molecular circadian clock releases metabolic and biosynthetic processes from circadian control, which may provide a distinct advantage to cancer cells.Copyright: © 2023 Cazarin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.