A study led by Ludwig Institute Scientific Director Chi Van Dang and colleagues at the University of Pennsylvania, the University of Rochester, The Wistar Institute and Johns Hopkins University described in an August paper in PLOS Genetics how the MYC oncogene interferes with the molecular clock in cells that governs their circadian rhythms. These are 24-hour rhythms that are woven into almost every aspect of cell biology—most notably metabolism and gene expression patterns—and are frequently disordered in cancer. Their disruption can, in fact, promote cancer initiation and progression. Using time-series RNA-sequencing and metabolomics in three distinct cancer cell lines, the researchers demonstrated that the heightened, oncogenic activation of MYC, which is a master regulator of cell metabolism, disrupts over 85% of oscillating, clock-associated genes. The oncogene enhanced the synthesis of proteins in both mitochondria and the cytoplasm of cells, stepped up the biochemical programs that drive biosynthesis and inhibited the mechanisms that govern the cell’s attachment to surfaces. It also altered the expression of proteins involved in importing nutrients, changed the balance of amino acids in cells and altered the times of day when the metabolism of amino acids and nucleic acids are at their peak. The findings suggest MYC-driven perturbations of the circadian clock release metabolic and biosynthetic processes from circadian control, potentially offering a metabolic advantage to cancer cells.
MYC disrupts transcriptional and metabolic circadian oscillations in cancer and promotes enhanced biosynthesis
PLOS Genetics, 2023 August 28