Tumor suppression by the molecular clock
How does the molecular clock interact with cancer? Does an active clock promote or suppress cancer formation? Many years of studies have shown that shift workers have a higher incidence of cancer, suggesting that a healthy circadian clock may be tumor-suppressive. Recent studies by our lab and other have suggested the same phenomenon in cancer cell lines and in mouse models of cancer.
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MYC disruption of the circadian metabolic cycle
One of the most important outputs of the clock is metabolic oscillation. How is metabolic oscillation affected by tumorigenesis? In the body, metabolic oscillations help us balance our food intake and energy expenditure with activity and rest. Cancer cells, in contrast, have a deregulated metabolism compared to their somatic counterparts. Tumor cells greatly increase both their nutrient uptake and biomass accumulation to fuel increased cell growth and division.
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Metabolic control of the molecular clock
The molecular clock and circadian rhythm are known to control metabolism, but does the molecular clock respond to metabolic cues? Does metabolic input feed back to control the molecular clock? This question is particularly important in the context of cancer, as new therapies targeting altered cancer cell metabolism are currently in clinical trial and due to enter the clinic soon.
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MYC and the clock in non-small cell lung cancer
MYC is amplified in lung cancer, but does it disrupt the clock in these tumors, and does this play a role in tumor progression? Non-small cell lung cancer (NSCLC) is the deadliest cancer in the United States, with the American Cancer Society estimating about 234,000 new cases in 2018, and 154,000 deaths. At least 8% of NSCLC has amplified MYC (accounting for more than 18,000 new cases per year), and while new targeted therapies for NSLCLC have entered the clinic in recent years, none of these therapies target MYC-amplified cancers, and the status of the molecular clock in these cancers is not currently known.
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Endogenous MYC and the molecular clock in cancer
While MYC is mutated, amplified, or translocated in many human cancers, in others it is overexpressed or stabilized downstream of other oncogenic mutations, and the role of MYC in control of the clock in these settings is unknown. For instance, mutated RAS, common in a variety of cancers, prevents MYC protein degradation. Endogenous MYC, unlike mutated MYC, circadian-controlled and oscillates at the mRNA and protein level, so it remains unclear how endogenous MYC stabilized or overexpressed downstream of other oncogenic mutations may affect the molecular clock.
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