Some studies have found that staying up late, increases the risk of cancer. Biologists at MIT have now discovered an association that could explain this increased risk. In humans and most other organisms, a biological clock, governed by light, regulates key aspects of human physiology by controlling cellular activities that include metabolism and cell division. In mouse studies, the MIT team found that two of the genes that control cellular biological rhythms also have a role as tumor suppressors. Loss of these tumor suppressor genes, either through genetic elimination or disruption due to the normal light/dark cycle, would make the tumors more aggressive. Disruption of the biological clock The central human biological clock, located in the brain’s suprachiasmatic nucleus (SCN), receives light information from the retina. the SCN communicates its information to cells via hormones and other signaling molecules. Within the cell, a gene called BMAL1 is responsible for activating other genes that control circadian activity, including a gene called Per2. Protein levels encoded by these genes normally fluctuate throughout the day, but when the normal light/dark cycle is disrupted, these fluctuations disappear. “Cells need light cues; it’s like a clock needing a reset button. When something that indicates that is lost, every cell in your body loses its normal rhythm.” He and his colleagues set out to investigate a possible link between cancer and these genes in mice that had been genetically modified to develop a form of cancer known as non-small cell lung cancer. To begin, they exposed the mice to two different light/dark schedules. One group of mice was housed together with the same day and night schedule as normal – 12 hours of light followed by 12 hours of darkness – while the other group received a “jet lag” schedule: every two to three days, they were exposed to light for eight more hours. This mimics the disruption of the biological clock that occurs in humans when they work at night or travel through multiple time zones. As a result, the tumors in the second group of mice grew much faster than those in the first group. In their next set of experiments, the researchers will continue to subject the mice to a normal light/dark schedule, but will knock out the BMAL1 and Per2 genes. In those mice, the tumors grew faster, just as they did in the “jet lag” schedule. “If you disrupt these genes in every cell in your body, you usually can’t take advantage of the light you receive,” Papagiannakopoulos says. “It’s like breaking a biological clock with a molecular hammer.” Out-of-control growth The BMAL1 and Per2 genes control the timing of the production of an oncogenic protein called c-myc, so when these genes are disrupted, c-myc begins to accumulate, stimulating cell metabolism and accelerating proliferation. the C-myc gene turns on this program that allows cells to produce more metabolites, more nutrients and more of the raw materials needed for new cell production. It is important for the ability of cells to proliferate. Joseph Takahashi is the department chair of the Division of Neuroscience at the University of Texas Southwestern Medical Center. He was not personally involved in the experiment, but says, “This study shows us an important link between cancer and biological clock dysfunction. This work is very clear and definitive, and it is exactly what we need to elucidate the possible inhibitory effects of the biological clock on benign and malignant tumors.” The MIT researchers also analyzed human lung tumor samples, and they found that the BMAL1 and Per2 genes, as well as other key biological clock genes, were expressed at lower levels in lung tumor tissue than in healthy tissue. The expression levels of these genes were even lower in the most aggressive tumors.Papagiannakopoulos is currently investigating whether weaknesses occur after disrupting the biological clock of cells, such as cancer cells, through, for example, loss of the BMAL1 and Per2 genes? And whether these weaknesses could potentially be exploited as potential drug targets. He also plans to study how disruption of circadian rhythms affects other types of cancer, including pancreatic cancer.