A Time for MYC: Metabolism and Therapy

Abstract

The MYC oncogene is frequently deregulated in human cancers, whereas the proto-oncogene is exquisitely, tightly regulated in normal cells. Deregulated MYC drives transcriptional imbalance, thereby altering metabolism and disrupting the circadian Bmal1-Clock E-box-dependent transcriptional circuitry. Sustained oncogenic MYC expression drives a constitutive growth program with mammalian target of rapamycin (mTOR) activation that renders cells dependent on nutrients, such that glucose or glutamine deprivation could trigger cell death and key enzymes such as lactate dehydrogenase A (LDHA) and glutaminase (GLS) amenable for targeting in cancers. Further, MYC-mediated suppression of the circadian clock is surmised to suspend the inhibitory effect of Bmal1-Clock on metabolism, allowing for MYC-driven cancer cells to reach a higher state of anabolic metabolism. Hence, metabolic therapy could be deployed, particularly at specific times of the day, to diminish side effects to normal tissues while maintaining antitumor efficacy.