Discovery could increase tumors’ sensitivity to radiation therapy

To make tumors more sensitive to the killing power of radiation is a key aspiration for many radiation oncologists. Researchers at Washington University School of Medicine in St. Louis have uncovered new information that leads them closer to that goal.

Mouse embryos stained to show MOF (green) and its histone tag (red) demonstrate that MOF is essential for cell proliferation. Embryos that don’t have the gene for MOF (bottom row) are beginning to die by the time they reach the 32-cell stage of development.

In an upcoming issue of the journal Molecular and Cellular Biology that is currently available online, they report the first extensive study of an enzyme called MOF that helps control how DNA is packaged in cells. The researchers show that MOF is an essential factor for tumor development, and they say it may be possible to manipulate the enzyme to make tumors more sensitive to radiation therapy.

MOF adds a tag — a special chemical group — to the spools that hold the long strands of DNA in the chromosomes. The spools, made of proteins called histones, pack the genetic material into a more condensed form. By adding a tag at a precise location on one kind of histone, MOF helps relax the tight packing of genes and thereby influences how active the genes are.

Although many enzymes are involved in controlling chromosome structure to maintain cells’ genetic machinery, MOF is so essential that without it cells inevitably die.

“We think that if we can deplete MOF in tumor cells, but not in healthy cells, we will gain a therapeutic advantage,” says Tej K. Pandita, Ph.D., associate professor of radiation oncology and of genetics and a researcher with the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital. “If we affect MOF in tumor cells, they will be weakened and unable to recover after radiation exposure.”

Tej Pandita
Tej Pandita

Pandita and his group at the School of Medicine focus their research on ways to increase the radiation sensitivity of cancer cells to enhance the cure rate of radiation therapy. They became interested in MOF because it was previously found to be involved in genomic instability and defective DNA damage repair.

Other studies have suggested that loss of the histone tag created by MOF is a hallmark of cancerous cells. In contrast, in this study an analysis of more than 300 tumor samples demonstrated that all tumors had either normal or increased amounts of MOF and its histone tag compared to normal samples. When the researchers caused MOF to be more abundant than usual in cells, the cells proliferated faster and showed telltale signs of cancerous transformation. When the same cells were injected into mice, tumors from cells that had an overabundance of MOF grew faster than other tumor cells.

The study also demonstrated that cells with less MOF were more sensitive to radiation exposure. Now the researchers are trying to identify inhibitors of MOF that block its ability to tag histones specifically in tumor cells. “Our research on MOF shows that it is a component that is absolutely needed for cells to proliferate,” Pandita says. “It could be the Achilles’ heel of cancerous growth.”

The research group plans further studies that will clarify how MOF functions and what other cellular components it interacts with. “Using this kind of information, we can more logically approach the issue of making cancerous cells more sensitive to radiation,” Pandita says. “Our aim is to achieve a balanced therapeutic adjunct that can keep normal tissue healthy while weakening tumor cells.”

The research also demonstrated that MOF is vital for the development of embryos. It showed that primitive cells, called stem cells, in mouse embryos have high amounts of MOF, and without MOF they stopped growing.

Like cancer cells, stem cells divide rapidly. “Evidence is accumulating to suggest that cancer cells could be considered aberrant stem cells,” Pandita says. “MOF is a factor that is common to both embryonic stem cells and cancer cells and ensures their ability to proliferate rapidly.”

Gupta A, Guerin-Peyrou TG, Sharma GG, Park C, Agarwal M, Ganju RK, Pandita S, Choi K, Sukumar S, Pandita RK, Ludwig T, Pandita TK. Mammalian ortholog of Drosophila MOF that acetylates histone H4 lysine 16 is essential for embryogenesis and oncogenesis. Molecular and Cellular Biology Oct. 29, 2007 (advance online publication).

Funding from the National Institutes of Health, the Department of Defense and the Department of Radiation Oncology at Washington University supported this research.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Siteman Cancer Center is the only federally-designated Comprehensive Cancer Center within a 240-mile radius of St. Louis. Siteman Cancer Center is composed of the combined cancer research and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine. Siteman has satellite locations in West County and St. Peters, in addition to its full-service facility at Washington University Medical Center on South Kingshighway.