Cancers don't sleep: The Myc oncogene can disrupt circadian rhythm

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.

Timing of the body's molecular clock in normal cells synchronizes the cellular need for energy with food intake during our sleep-wake cycle. Timing matters to the study of cancer in two ways. First, toxicity to some is related to time of day. For example, a cancer drug called 5-flourouracil is less toxic if given to a patient at night because the that detoxify it are more abundant at night.

Second, several circadian rhythm genes have been implicated as tumor suppressors, although those exact connections are as yet unclear. Other researchers have also observed that many, but not all, cancer lack proper circadian rhythm.

"Our hypothesis is that disrupting circadian rhythm benefits cancer cells by unleashing their metabolism from the constraints of the molecular clock," says Altman. "In this regard, cancers don't sleep; they don't rest."

The Penn study deals with the relationship of clock proteins in 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 .

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 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 treatment strategies that reduce side effects and increase effectiveness" says Hsieh.

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

Related Stories

Research team shows skin stem cells run by circadian clock

Nov 10, 2011

(PhysOrg.com) -- Most everyone has heard of the circadian rhythm or the internal clock that people have that tells them when to do things, such as go to sleep. In fact, researchers have actually located where this “clock” ...

Major cancer protein amplifies global gene expression

Sep 27, 2012

Scientists may have discovered why a protein called MYC can provoke a variety of cancers. Like many proteins associated with cancer, MYC helps regulate cell growth. A study carried out by researchers at the National Institutes ...

Recommended for you

Pepper and halt: Spicy chemical may inhibit gut tumors

10 hours ago

Researchers at the University of California, San Diego School of Medicine report that dietary capsaicin – the active ingredient in chili peppers – produces chronic activation of a receptor on cells lining ...

Expressive writing may help breast cancer survivors

12 hours ago

Writing down fears, emotions and the benefits of a cancer diagnosis may improve health outcomes for Asian-American breast cancer survivors, according to a study conducted by a researcher at the University of Houston (UH).

Taking the guesswork out of cancer therapy

17 hours ago

Researchers and doctors at the Institute of Bioengineering and Nanotechnology (IBN), Singapore General Hospital (SGH) and National Cancer Centre Singapore (NCCS) have co-developed the first molecular test ...

Brain tumour cells found circulating in blood

18 hours ago

(Medical Xpress)—German scientists have discovered rogue brain tumour cells in patient blood samples, challenging the idea that this type of cancer doesn't generally spread beyond the brain.

International charge on new radiation treatment for cancer

19 hours ago

(Medical Xpress)—Imagine a targeted radiation therapy for cancer that could pinpoint and blast away tumors more effectively than traditional methods, with fewer side effects and less damage to surrounding tissues and organs.

User comments