News Release
  April 9, 2013

CONTACT:

Karen Kreeger

215-349-5658
karen.kreeger@uphs.upenn.edu

Perelman School of Medicine


This release is available online at
http://www.uphs.upenn.edu/news/News_Releases/2013/04/altman/

Cancers Don't Sleep: The Myc Oncogene Can Disrupt Circadian Rhythm

WASHINGTON, D.C. — The Myc oncogene can disrupt the 24-hour internal rhythm in cancer cells. Postdoctoral fellow Brian Altman, PhD, and graduate student Annie Hsieh, MD, both from the in the lab of Chi Van Dang, MD, PhD, director of the Abramson Cancer Center, Abramson Family Cancer Research Institute, Perelman School of  Medicine, University of Pennsylvania, present their data in the “Metabolic Pathway Regulation in Cancer” session at the 2013 American Association for Cancer Research meeting, Washington, D.C., April 9, 2013.

The Penn study deals with the relationship of clock proteins in peripheral tissues associated with three types of cancer cells. The researchers surmise that Myc may affect circadian rhythm by promiscuously binding to promoter regions in key genes for maintaining circadian rhythm. In fact, using a well known genome browser they confirmed that Myc binds to circadian genes.

The Penn team also found that Myc upregulates another clock-regulated protein called NAMPT, potentially leading to dysregulated Sirt1 activity, another protein that is part of the complicated molecular clock.

Inhibiting NAMPT downstream of Myc also led to changes in circadian gene expression, suggesting a role for the modulation of other proteins downstream of Myc in throwing a wrench in the clock’s gears.

Using cells from cultures of neuroblastoma, osteosarcoma, and hepatocellular carcinoma, which all overexpress Myc, they found that the abundance of Myc specifically upregulated the circadian protein Rev-erbα. This protein in turn suppressed the oscillation of Bmal1 messenger RNA and decreased expression of the main clock protein Bmal1.

What’s more, the disrupted circadian oscillations in the Myc-expressing cancer cells could be partially rescued by inhibiting expression of Rev-erbα.

“Our data suggest that Myc-driven cancers have altered circadian oscillation due to upregulation of Rev-erbα and NAMPT, and that these Myc cancers may be good candidates for chronotherapy,” says Altman. “This work ties together the study of cell metabolism and cancer chronotherapy – If cells don’t have to ‘rest,” they may replicate all the time, with no breaks at all.“

“The understanding of these basic mechanisms from our work should lead to better cancer treatment strategies that reduce side effects and increase effectiveness” says Hsieh.

This study was funded by the National Cancer Institute (R01CA051497, R01CA57341) and the Leukemia and Lymphoma Society (636311).

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Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

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