Abstract
The MYC oncoprotein and its family members N-MYC and L-MYC are known to drive a wide variety of human cancers. Emerging evidence suggests that MYC has a bi-directional relationship with the molecular clock in cancer. The molecular clock is responsible for circadian (~24 h) rhythms in most eukaryotic cells and organisms, as a mechanism to adapt to light/dark cycles. Disruption of human circadian rhythms, such as through shift work, may serve as a risk factor for cancer, but connections with oncogenic drivers such as MYC were previously not well understood. In this review, we examine recent evidence that MYC in cancer cells can disrupt the molecular clock; and conversely, that molecular clock disruption in cancer can deregulate and elevate MYC. Since MYC and the molecular clock control many of the same processes, we then consider competition between MYC and the molecular clock in several select aspects of tumor biology, including chromatin state, global transcriptional profile, metabolic rewiring, and immune infiltrate in the tumor. Finally, we discuss how the molecular clock can be monitored or diagnosed in human tumors, and how MYC inhibition could potentially restore molecular clock function. Further study of the relationship between the molecular clock and MYC in cancer may reveal previously unsuspected vulnerabilities which could lead to new treatment strategies.
Highlights
Introduction to MYC and the MolecularCircadian Clock in Normal Cellular BiologyThe MYC family of proto-oncogenes is a group of protein-coding transcription factors whose effects extend to various biological processes, including cell cycle progression and metabolic control
Oncogenic MYC can shape the tumor immune microenvironment to support influx drive recruitment of mast cells that participate in angiogenesis [129], and it was more recently shown in a non-small cell lung cancer model that amplified MYC, in cooperation with mutated oncogenic K-RAS, drove depletion of T cells and natural killer (NK) cells from the tumor which corresponded with intra-tumoral accumulation of pro-tumirogenic CD206+ macrophages with elevated expression of PD-L1 [123]
While it is clear that oncogenic MYC can affect the molecular clock of tumor cells, it is less clear how MYC can influence the clock of tumor-infiltrating immune cells
Summary
The MYC family of proteins is upregulated in a the large number ofClock human theMYC’s manner of this upregulation, andClock whether it is direct indirect, Influence on the Molecular in Somatic. MYC bound to MIZ1 and antagonized its transcriptional activity, molecular clock function was ablated [36,37,38] These two groups of studies showed that MYC suppressed BMAL1 across a wide range of cancers, including osteosarcoma, neuroblastoma, hepatocellular carcinoma, Burkitt’s lymphoma, and T cell acute lymphoblastic leukemia [34,35,36,37,38]. This can be seen most clearly in PER2mutant overexpression in the liver, and Cry deletion in mouse fibroblasts [60,61] In both these cases, MYC was upregulated at least 25-fold as compared to wild-type cells; because neither Per mutation nor Cry deletion ablated the molecular clock, MYC continued to oscillate [60,61]. The authors noted that BMAL1 bound to the promoter of MYC in GSCs [68], but did not show whether MYC oscillated, which may be an intriguing topic of future study
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