Abstract 4616: Oncogenic c- and N-Myc disrupt circadian rhythm.

Abstract Circadian rhythms are regulated by feedback loops comprising a network of factors that regulate Clock-associated genes. Chronotherapy seeks to take advantage of altered circadian rhythms in some cancers to better time administration of treatments to increase efficacy and reduce toxicity. Taking advantage of cancers that have substantially different circadian rhythms, or are ‘out of phase’, with normal tissues, could open a wide therapeutic window to make them vulnerable to chemotherapy or targeted drugs at different times than normal tissue. However, there is currently no basis to identify which cancers have disrupted circadian rhythms and would be amenable to chronotherapy. c- and N-Myc are oncogenic transcription factors translocated or amplified in many cancers. While the role of Myc in circadian rhythm is currently unknown, it may affect circadian rhythm by binding to the same E-box promoter regions used by the central regulators of circadian rhythm, Clock/Bmal1. Additionally, Myc increases NAD+ levels through upregulation of NAMPT, and NAD+ is a crucial cofactor in the activity of the circadian regulator Sirt1. Thus, we hypothesized that Myc may disrupt circadian rhythm through two mechanisms: inappropriate engagement of E-box promoters and also upregulation of NAMPT leading to dysregulated Sirt1 activity. Here we show in neuroblastoma, osteosarcoma, and hepatocellular carcinoma cells that overexpressed Myc specifically upregulated the negative circadian regulator Rev-erbα, which in turn decreased expression of Bmal1. Inhibition of NAMPT downstream of Myc upregulation also led to major perturbations in circadian gene expression, suggesting a role for NAD modulation downstream of Myc in disruption of circadian rhythm. Importantly, My-expressing cells showed dramatically disrupted circadian oscillations, which could be partially rescued by inhibiting expression of Rev-erbα. Together, these data suggest that Myc-driven cancers have altered circadian oscillation due to upregulation of Rev-erbα and NAMPT, and that cancers driven by Myc may thus be good candidates for chronotherapy. We thank the following funding sources: NIH R01CA051497, R01CA57341, LLS 636311 Citation Format: Brian J. Altman, Annie Hsieh, Arvin Gouw, Anand Venkataraman, Bo Li, David Bellovin, M. Celeste Simon, Dean Felsher, John Hogenesch, Chi V. Dang. Oncogenic c- and N-Myc disrupt circadian rhythm. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4616. doi:10.1158/1538-7445.AM2013-4616