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SO ENDS this first of two weekends on an article about the relationship of the cellular circadian clock to cancer formation from the epidemiological and genetic evidence. Strange work hours have long been considered unhealthy, but this review compellingly suggests that it is actually carcinogenic. It is curious that it involves the circadian clock, and that it is so delicately balanced between health and disease. View in LinkedIn

GENE REWIRING. “It is thus tempting to speculate that a rewiring could take place during tumorigenesis, whereby the balance of clock-controlled transcription can be lost and consequently compensated for by oncogenic MYC signaling.” https://www.nature.com/articles/s41591-018-0271-8?fbclid=IwAR01C2Z4J5lxVYDLhxIb9dPb3fhNSZSxwimZvhHaJ4n3-nVPpkt2PNqoukk View in LinkedIn

“CLOCK, BMAL1, and MYC are all transcription factors that share a highly similar basic helix-loop-helix (bHLH) protein domain, allowing these proteins to recognize the same promoter element, the enhancer box (E-box) sequence, in the regulatory regions of target genes.” https://www.nature.com/articles/s41591-018-0271-8?fbclid=IwAR01C2Z4J5lxVYDLhxIb9dPb3fhNSZSxwimZvhHaJ4n3-nVPpkt2PNqoukk View in LinkedIn

VALIDATION. “These findings in cells cultured in vitro have been further validated in vivo via genetically engineered mice.” https://www.nature.com/articles/s41591-018-0271-8?fbclid=IwAR01C2Z4J5lxVYDLhxIb9dPb3fhNSZSxwimZvhHaJ4n3-nVPpkt2PNqoukk View in LinkedIn

DYSBALANCE. “It is tempting to speculate that altered metabolism could provide feedback to cellular growth and clock function, contributing to the unbalanced state characteristic of tumor cells.” https://www.nature.com/articles/s41591-018-0271-8?fbclid=IwAR01C2Z4J5lxVYDLhxIb9dPb3fhNSZSxwimZvhHaJ4n3-nVPpkt2PNqoukk View in LinkedIn

CLOCK METABOLISM. “Given that the clock is intimately involved in regulating metabolism in peripheral tissues, and the majority of metabolites in liver and serum are controlled in a cyclic manner, the intersection of cancer metabolism and its control by the circadian clock is an area of active investigation.” https://www.nature.com/articles/s41591-018-0271-8?fbclid=IwAR01C2Z4J5lxVYDLhxIb9dPb3fhNSZSxwimZvhHaJ4n3-nVPpkt2PNqoukk View in LinkedIn

TIMING PACEMAKER. “Collectively these findings implicate a critical signaling axis that coordinates the central pacemaker with peripheral circadian transcription and metabolism, though the implications of these findings in humans remains unresolved (Box 2).” https://www.nature.com/articles/s41591-018-0271-8?fbclid=IwAR01C2Z4J5lxVYDLhxIb9dPb3fhNSZSxwimZvhHaJ4n3-nVPpkt2PNqoukk View in LinkedIn

LAG MECHANISM. “Jet lag operates by disrupting both circadian gene expression programs as well as circadian metabolism in the liver, and central to this rewiring is an induction of hepatic cholesterol and bile acid levels, which activate the oncogenic program of the nuclear receptor constitutive androstane receptor (CAR), and downstream activation of β-catenin.” https://www.nature.com/articles/s41591-018-0271-8?fbclid=IwAR01C2Z4J5lxVYDLhxIb9dPb3fhNSZSxwimZvhHaJ4n3-nVPpkt2PNqoukk View in LinkedIn

JET LAG. “Recent laboratory data have shed light on the molecular mechanisms of circadian disruption through jet lag and its link with tumorigenesis. Long-term jet lag initiates a program of nonalcoholic fatty liver disease (NAFLD) that progresses to steatohepatitis, fibrosis, and eventually HCC in mice.” https://www.nature.com/articles/s41591-018-0271-8?fbclid=IwAR01C2Z4J5lxVYDLhxIb9dPb3fhNSZSxwimZvhHaJ4n3-nVPpkt2PNqoukk View in LinkedIn

EPIGENETIC SILENCERS. “Moreover, in 126 cases of several types of hematologic malignancies, Bmal1 gene silencing due to CpG promoter methylation was found in 19.7% of diffuse large B cell lymphomas, 33.3% of acute lymphocytic leukemias, and 19.2% of acute myeloid leukemias.” https://www.nature.com/articles/s41591-018-0271-8?fbclid=IwAR01C2Z4J5lxVYDLhxIb9dPb3fhNSZSxwimZvhHaJ4n3-nVPpkt2PNqoukk View in LinkedIn