MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells

• Published in: Cell metabolism Vol. 22; no. 6; pp. 1009 - 1019
• Main Authors: Altman, Brian J., Hsieh, Annie L., Sengupta, Arjun, Krishnanaiah, Saikumari Y., Stine, Zachary E., Walton, Zandra E., Gouw, Arvin M., Venkataraman, Anand, Li, Bo, Goraksha-Hicks, Pankuri, Diskin, Sharon J., Bellovin, David I., Simon, M. Celeste, Rathmell, Jeffrey C., Lazar, Mitchell A., Maris, John M., Felsher, Dean W., Hogenesch, John B., Weljie, Aalim M., Dang, Chi V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2015
• Subjects: ARNTL Transcription Factors - chemistry; ARNTL Transcription Factors - genetics; ARNTL Transcription Factors - metabolism; Base Sequence; Binding Sites; Cell Line, Tumor; Circadian Rhythm; CLOCK Proteins - chemistry; CLOCK Proteins - genetics; CLOCK Proteins - metabolism; Dimerization; Genes, Reporter; Glucose - metabolism; Glutamine - metabolism; Humans; Nuclear Receptor Subfamily 1, Group D, Member 1 - antagonists & inhibitors; Nuclear Receptor Subfamily 1, Group D, Member 1 - genetics; Nuclear Receptor Subfamily 1, Group D, Member 1 - metabolism; Period Circadian Proteins - genetics; Period Circadian Proteins - metabolism; Promoter Regions, Genetic; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA Interference; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2015.09.003

The MYC oncogene encodes MYC, a transcription factor that binds the genome through sites termed E-boxes (5′-CACGTG-3′), which are identical to the binding sites of the heterodimeric CLOCK-BMAL1 master circadian transcription factor. Hence, we hypothesized that ectopic MYC expression perturbs the clock by deregulating E-box-driven components of the circadian network in cancer cells. We report here that deregulated expression of MYC or N-MYC disrupts the molecular clock in vitro by directly inducing REV-ERBα to dampen expression and oscillation of BMAL1, and this could be rescued by knockdown of REV-ERB. REV-ERBα expression predicts poor clinical outcome for N-MYC-driven human neuroblastomas that have diminished BMAL1 expression, and re-expression of ectopic BMAL1 in neuroblastoma cell lines suppresses their clonogenicity. Further, ectopic MYC profoundly alters oscillation of glucose metabolism and perturbs glutaminolysis. Our results demonstrate an unsuspected link between oncogenic transformation and circadian and metabolic dysrhythmia, which we surmise to be advantageous for cancer. [Display omitted] •The MYC and MYCN oncogenes disrupt the circadian molecular clock•MYC directly activates negative regulators of BMAL1-CLOCK•Constitutive activation of negative regulators, REV-ERBs, suspends the clock•Clock suspension is associated with disruption of circadian metabolic oscillation Altman et al. show that oncogenic MYC disrupts the molecular clock and alters circadian glucose metabolism and glutaminolysis in favor of growth-related biosynthesis in cancer cells. Both MYC and N-MYC upregulate REV-ERBα, which suppresses BMAL1 expression and oscillations. High REV-ERBα or low BMAL1 predicts poor clinical outcome in N-MYC-driven human neuroblastomas.