부산대학교 도서관

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. Author summary: Circadian rhythms are 24h-day/night cycles that temporally compartmentalize cellular, biochemical, physiological, and behavioral processes. These oscillations are generated by a set of ubiquitous proteins that compose the "molecular clock". Dysfunctional circadian rhythms are associated with pathologies including cancer. The oncogene MYC, which is frequently altered in human cancers, interferes with the molecular clock. However, it is still not fully understood how MYC impacts these oscillations and how this could support cancer development. Using time-series RNA-sequencing and metabolomics in three distinct cancer cell lines, we demonstrated that MYC upregulation in cancer cells disrupted over 85% of oscillating genes. MYC triggered enhanced ribosomal and mitochondrial biogenesis while concurrently inhibiting cell attachment pathways. Intriguingly, MYC activation reshaped biosynthetic programs, stimulating their continuous upregulation. Furthermore, MYC altered nutrient transporter proteins, leading to increased expression and altered amino acid levels. MYC also changed the time of the day in which metabolites related to amino acid and nucleotide metabolism peaked in cancer cells. Collectively, our findings indicate that MYC-driven perturbations of the circadian clock release metabolic and biosynthetic processes from circadian control, potentially offering a metabolic advantage to cancer cells. This study sheds new light on the intricate interplay between molecular circadian regulation and cancer metabolism. [ABSTRACT FROM AUTHOR]