It has been well established for decades that a master clock within the brain, tuned to the daily phases of light and dark, drives fluctuations in gene activity and protein levels that give rise to daily cycles in virtually every aspect of human physiology. What has been more elusive to scientists is the connection between disrupting the body’s circadian rhythm and progression of various disease states, especially cancer.
However, a new study from scientists at the University of California, Santa Cruz has found that a protein commonly associated with cancer cells is a potent suppressor of the circadian clock—providing a new mechanistic link between cancer and disruption of the master clock function.
“The clock is not always disrupted in cancer cells, but studies have shown that disrupting circadian rhythms in mice causes tumors to grow faster, and one of the things the clock does is set restrictions on when cells can divide,” explained Carrie Partch, Ph.D., professor of chemistry and biochemistry at UC Santa Cruz and senior author on the current study.
The findings from this study were published online today in Molecular Cell through an article entitled “Cancer/Testis Antigen PASD1 Silences the Circadian Clock.”
Dr. Partch and her colleagues focused their attention on a protein called PASD1, which has been shown previously to be expressed on a wide array of cancer cells, including melanoma, breast, and lung cancer. PASD1 is a part of a larger group of proteins known as cancer/testis antigens that are typically expressed in germ line cells, which produce sperm and eggs.
“For very few of these do we understand the roles they might play in driving cancer,” stated Dr.Partch. “Understanding how PASD1 is regulating the circadian clock could open the door to developing new therapies. We could potentially find ways to disrupt it in those cancers in which it is expressed.”
Specifically, the UC Santa Cruz team was able to uncover how PASD1 was able to interact with the molecular mechanisms inherent to the biological clock. The circadian rhythm is regulated through a feedback loop controlled by the interaction of four main genes and the proteins they encode. The proteins CLOCK and BMAL1 initially combine to turn on the Period and Cryptochrome genes. The Period and Cryptochrome proteins eventually combine to turn off the genes for CLOCK and BMAL1. Dr. Partch’s team found that PASD1 is structurally similar to the CLOCK protein and interferes with the CLOCK-BMAL1 complex.
“It shuts the clock off very efficiently,” Dr. Partch said.
Additionally, using RNA interference techniques the investigators were able to block PASD1 expression in cancer cells and observe that the clock cycle was turned back on within those cells.
“By understanding what makes the clock tick and how it is regulated, we may be able to identify points where we can intervene pharmacologically to treat disorders in which the clock is disrupted,” Dr. Partch said.
Dr. Partch's lab is continuing to investigate the biochemical mechanisms involved in the protein's interactions with the molecular clock, with the hope that an even stronger link with the initiation and progression of cancerous phenotypes can be uncovered and exploited therapeutically.
“There are vast consequences to trying to live outside the natural daily cycle,” Dr. Partch explained. “We know that clock disruption in general is not a good thing, and we have ongoing studies to explore its role in cancer and other human health problems.”