Study uncovers new shortcut mechanism behind cancer cell division

Living cells are one of the few materials that can replicate themselves, and this is crucial for tissue development and recovering from injury or illness. But making sure cell division only happens at the right time is essential, otherwise unregulated replication can lead to problems like cancer.

Researchers at the University of California, Santa Cruz, are studying how cells know when and how to divide, and the influence on these processes of genes known to be important in cancer.

A new study published in The EMBO Journal finds that a gene affected in many cancers, known as E2F1, can cause cells to divide without having to abide by the normal rules of cell division. Instead of having to unpack the genetic material inside the cell, E2F1 takes a shortcut path by binding directly to a small area of the DNA that remains tightly packaged inside the cell. 

This discovery helps further illuminate the processes that drive cell proliferation and may influence the growth of cancer, with potential to help design more precise and targeted treatments.

Reprogramming cell fate

Associate Professor of Biomolecular Engineering at the Baskin School of Engineering Ali Shariati conducted this research alongside Professor Chemistry & Biochemistry Seth Rubin. Rubin's lab focuses on the biochemistry and gene expression of cell division, while Ali Shariati's lab studies how cells translate input from the body in order to decide whether or not to divide. Former BME postdoctoral scholar Gerrald Lodewijk, who is now a staff scientist at biotech company Ilumina, led the project.

Nearly all cells have the ability to divide, but the majority don't, instead waiting in a state similar to hibernation. And this hibernation doesn't happen automatically-the body must constantly send signals to prevent cell division. Otherwise, any body part could grow bigger than its proper size, or grow tumors or cancer. 

Cells can't just rely on the assumption that they will stop dividing. The cells need to actively say, 'this is the liver, it should be this large, and after we reach this critical size, let's just stop dividing,' That's called homeostatic behavior, and that's not a trivial task for the body. It's a state where the cells are ready to be activated, but normally aren't, unless there is an external requirement. It's a delicate balance to maintain." 

Ali Shariati, Associate Professor of Biomolecular Engineering at the Baskin School of Engineering

To recover from injuries or illness, the body can send a signal to cells to leave hibernation and divide. To do so, it must instruct cells to physically unpack the DNA that is tightly wrapped around proteins inside its nucleus -a process well documented in biology textbooks. To recreate this process in the lab, scientists typically add nutrients and growth signals to dormant cells, which cause them to divide.

The UC Santa Cruz researchers studied an important gene called E2F1, which is central for cell division and malfunctions in many cancers. Other scientists have found that the activation of this gene can cause cells to divide without growth signals, and the UCSC scholars further confirmed this finding. 

Then, the research team discovered that E2F1 appears to be taking a shortcut method to cause division. Using a very limited amount of physical space in the genome, the E2F1 protein can bind directly to the genome in order to switch on the genes related to cell division. 

"The surprising part is, unlike the typical process, E2F1 is able to activate the cell cycle genes without physically unpacking the genome much or at all," Shariati said. "That means this is a new way of transcription factors being able to activate genes and let the cells completely change their fate and go on to divide."

The ability to activate cell division makes E2F1 similar to a special category of genes that scientists call "pioneer factors," which can unlock tightly packed DNA to fundamentally reprogram cells. This special status indicates that cells must maintain a precise level of E2F1 to maintain proper cell division. Indeed, the UC Santa Cruz researchers found that cells can sense a specific threshold of E2F1: once levels cross that line, dormant cells begin to divide.

E2F1 and cancer

E2F1's shortcut method of division has its own limitations. The scientists found that cells can only divide at most three times without any additional growth signals. To study cell division over time, the researchers used live single-cell imaging techniques developed in the Shariati lab, including their in-house DeepSea software.

Nonetheless, the shortcut method to cell division that E2F1 uses happens much faster than the typical process with nutrients. Researchers suspect cancer cells may exploit this E2F1 activity, although more research will be needed to better understand how this mechanism works. 

"Cancers may overcome the typical checks and balances that our cells are using to maintain a dormant state, dysregulating and increasing the level of E2F1 to find a shortcut back to the cell cycle," Shariati said. 

Shariati plans to further study how exactly E2F1 activates the genes after it binds to the genome. This could help to find a more precise and targeted approach for interfering with this pathway in the context of cancer. He also wants to study the 8 genes in the same family as E2F1, some of which cause cells to become dormant, and their role in cancer. 

Rubin is also interested in whether E2F1 can be targeted in cancers. 

"There has been much effort in the field to target E2F1's role in cell division by inhibiting upstream proteins that control E2F1 activity," Rubin said. "We have been wondering whether there are ways to target E2F1 itself to stop cancer cells from proliferating. The first steps are figuring out what specific cancers would benefit from blocking E2F1 activity, and then finding molecules that bind and prevent E2F1 from activating cell cycle gene expression."