MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells

Brian J. Altman, Annie L. Hsieh, Arjun Sengupta, Saikumari Y. Krishnanaiah, Zachary E. Stine, Zandra E. Walton, Arvin M. Gouw, Anand Venkataraman, Bo Li, Pankuri Goraksha-Hicks, Sharon J. Diskin, David I. Bellovin, M. Celeste Simon, Jeffrey C. Rathmell, Mitchell A. Lazar, John M. Maris, Dean W. Felsher, John B. Hogenesch, Aalim M. Weljie, Chi V. Dang

Research output: Contribution to journalArticlepeer-review

127 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1009-1019
Number of pages11
JournalCell Metabolism
Volume22
Issue number6
DOIs
StatePublished - 2015
Externally publishedYes

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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