Cazarin Juliana, DeRollo Rachel E, Ahmad Shahidan Siti Noor Ain Binti, Burchett Jamison B, Mwangi Daniel, Krishnaiah Saikumari, Hsieh Annie L, Walton Zandra E, Brooks Rebekah, Mello Stephano S, Weljie Aalim M, Dang Chi V, Altman Brian J
Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
bioRxiv. 2023 Aug 8:2023.01.03.522637. doi: 10.1101/2023.01.03.522637.
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.
分子生物钟控制着健康组织中基因、蛋白质和代谢物的24小时节律性振荡，而在许多人类癌症中，这种生物钟被破坏。已证明MYC癌蛋白的失调表达会改变分子生物钟基因的表达，导致跨癌症类型的分子生物钟振荡紊乱。目前尚不清楚癌细胞从抑制生物钟振荡中获得了什么益处，以及这种分子生物钟振荡的丧失如何影响癌症中的全局基因表达和代谢。我们假设MYC或其旁系同源物N-MYC（本文统称为MYC）以静态、非振荡的方式抑制基因表达和代谢的振荡，从而上调参与生物合成的途径。为了验证这一点，我们使用时间序列RNA测序和代谢组学方法，检测了来自不同癌症类型且可诱导MYC的细胞，以确定MYC激活在多大程度上破坏基因、基因表达途径和代谢物的全局振荡。我们将分析重点放在多个癌细胞系模型中共同变化的基因、途径和代谢物上。我们在此报告，MYC破坏了超过85%的振荡基因，同时促进核糖体和线粒体生物合成增强，并抑制细胞附着途径。值得注意的是，当MYC被激活时，以前具有昼夜节律的生物合成程序转变为以无振荡的方式上调。此外，MYC的激活消除了营养转运蛋白的振荡，同时极大地上调了转运蛋白的表达、细胞表面定位和细胞内氨基酸池。最后，我们报告MYC破坏了代谢物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对分子生物钟的破坏使代谢和生物合成过程从昼夜节律控制中释放出来，这可能为癌细胞提供独特的优势。
