Pinpointing the chromosomal creation of cancer

Yoshiaki Azuma, Ph.D., associate professor of molecular biosciences at The University of Kansas and member of the Cancer Biology Research Program at The University of Kansas Cancer Center, is analyzing the role of an enzyme called Topoisomerase II (Topo II) and how it may affect the stability of genomes. Genomic instability, or a large amount of mutations with the genome of a cell, is a basic cause of cancer.

Topo II was previously only known to change how the two strands in DNA are intertwined (chromosome segregation); however, Dr. Azuma has found additional functions that may lead to a better understanding of how cancer mutations are born.

"Topo II is one of the well-established targets for cancer patients," said Dr. Azuma. " It also has a specific role in chromosome segregation in mitosis, which is not well understood on a molecular level."

His lab is collaborating with Duncan Clarke, Ph.D., at the University of Minnesota, who has created genetic models that show a particular mutation of Topo II created a unique defect in mitosis, or when a cell divides. Dr. Azuma is using the genetic models to investigate how SUMO (a type of protein that attaches and detaches itself from other proteins in cells to change their function) interplays with this mutation in Topo II. In turn, this change in Topo II may affect the regulation of Aurora B kinase, which is necessary for successful chromosome segregation and normal cell division.

Topo II is an essential protein necessary for normal cell division, but it is found to be over expressed in many types of cancers, including certain types of liver, breast, brain and skin cancers. SUMO modifies Topo II "during mitosis and mediates specific protein/protein interaction," said Dr. Azuma.

The relationship between the SUMO-modified Topo II and Aurora B kinase is important because high levels of Aurora B kinase cause unequal chromosome separation during cell division. This creates cells with an atypical number of chromosomes, which can cause cancer.

Dr. Azuma is creating a mutant form of Topo II that cannot be modified by SUMO. He will compare how this version of Topo II interacts with chromosomes during mitosis as opposed to Topo II that is modified by SUMO and causes mutations.

"Defective chromosome segregation results in loss or gain of an entire chromosome after cell division, which leads to chromosome instability, a hallmark of cancer," explained Dr. Azuma. "This suggests that the defective chromosome segregation could result in the loss of tumor suppressor genes and the gain of oncogenes after cell division."

He will use yeast and human cells to analyze how the chromosome segregation becomes defective by looking at how long it takes for the cells to divide. Once he understands more about how this mutant version of Topo II affects mitosis, he will see how Topo II-targeted drugs work against this version.

There are two current, effective drugs that are Topo II inhibitors -- Etoposide and Doxorubicin. A devastating side effect, however, is that they can sometimes cause leukemia as a secondary cancer because they stop cells from being able to repair DNA.

"Intriguingly, these drugs are also shown to increase the SUMO modification of Topo II in mitosis, suggesting SUMO modification affecting Topo II function can open the door to understanding why Topo II-targeted drugs induce leukemia as well as potential combination therapies for more effective use of these drugs."