Until now, global cancer research has focused on 2% of the human genome that make proteins. However, breakthrough research at the University of Newcastle and HMRI has established exciting possibilities with genes that were previously thought to be ‘non-functioning’ in cancer cells, following the discovery of two new pathways that could play a role in cancer treatments.
Dramatically reshaping the scope of cancer research, the discovery was made by investigating a special class of genes known as noncoding RNAs (ncRNA) found in the human genome (DNA). Led by Professor Xu Dong Zhang, Dr Lei Jin and Dr Rick Thorne from HMRI’s Cancer Research Program, identification of the two unique pathways could lead to the development of new, more targeted cancer therapies.
The first finding, recently published in the prestigious Nature Cell Biology journal, identified a particular ncRNA molecule responsible for protecting the genome.
Named GUARDIN by the pioneering scientists, the molecule helps to stabilise a particular protein involved in DNA repair processes.
“We discovered the protective mechanisms of GUARDIN were twofold. On one hand, it acts like a sponge to absorb harmful molecules. On the other, it functions like a bridge that brings two proteins together to protect the genome,” lead Investigator Professor Zhang, said.
Consequently, by reducing the presence of GUARDIN in the genome, cancer cells were made more vulnerable to common drug therapies that target DNA.
“For cells to survive they must maintain the integrity of their genome, their DNA. Many cancer treatments actually work through causing DNA damage and we found that depleting GUARDIN significantly enhanced the death of cancer cells caused by DNA damaging drugs,” co-author, Dr Jin, added.
The second finding, published in the Proceedings of the National Academy of Sciences (PNAS) journal earlier this year, investigated a ncRNA that regulates the metabolism of a cell and subsequently how it gets its energy.
“While normal cells use up oxygen for energy, cancer cells use a process called glycolysis to produce energy, which is essential for its survival. We found that ncRNA IDH1-AS1 accelerated the metabolic activity of cancer cells.
“At face value, glycolysis is not a particularly efficient way for cancer cells to make energy but there are other advantages, for example, producing building blocks that enable cell growth,” co-author Dr Thorne said.
“Like flicking a switch, we were encouraged that when we blocked IDH1-AS1, the cancer cell growth was also blocked and it began to revert to behave more like normal cells,” he added.
With many times more noncoding genes than coding genes, the findings have unlocked new avenues for research potential that could lead to a substantial increase of advanced and targeted treatment methods.
“Our findings have shown that ncRNA are functional and play a very important role in the regulation of biological processes, both physiological and pathological. We have only just touched the surface of how they work in the cell.
“There are currently no treatments anywhere in the world that target ncRNA, so this research presents promising potential for further studies and collaboration with pharmaceutical companies to design deliverable treatments that target these particular molecules,” Professor Zhang said.
Both studies were carried out in collaboration with a research team led by Professor Mian Wu from the University of Science and Technology in China.
* Professor Zhang, Dr Jin and Dr Thorne are members of the Hunter Cancer Research Alliance (HCRA) group, a collaborative partnership between the Hunter Medical Research Institute (HMRI), the University of Newcastle, Hunter New England Health and the Calvary Mater Newcastle.