Gene-ius!
Colon cancer has been on the rise in Americans under 50 for the last three decades, but it’s not exactly clear why. Researchers suspect poor diet, obesity, sedentary lifestyles, environmental exposures and genetics may be factors.
Now, scientists from Johns Hopkins University confirm that a particular gene may be fueling colon cancer, especially among younger people — and they are looking for ways to turn it off.
HMGA1 acts like a molecular “key” that “opens” regions of DNA to activate genes crucial for the proper functioning of colon stem cells. These stem cells are essential for continuously repairing and replacing the lining of the colon that naturally wears down from digestion.
Epigenetic regulators like HMGA1 are known to respond to stressors like genetic mutations, infection and inflammation triggered by a poor diet — overactivation of HMGA1 can lead to tumors.
“By opening up regions of the genome, HMGA1 allows other proteins to jump onto DNA and activate stem cell gene expression in an uncontrolled fashion,” explained Dr. Linda Resar, professor of medicine, pathology and oncology at the Johns Hopkins Kimmel Cancer Center.
HMGA1 directly activates ASCL2, a gene associated with early-onset colon cancer.
Also, high levels of HMGA1 may help tumor cells evade detection by immune cells, making cancer harder to fight.
Resar’s team wanted to see what would happen if they blocked HMGA1 activity in mice with mutations in the adenomatous polyposis coli (APC) gene. A mutation in this gene greatly increases the risk of colorectal cancer.
One set of mice had a copy of the mutant APC gene and a gut full of inflammatory bacteria, an environment known to promote cancer growth.
The other set of mice had two copies of the mutant gene.
Turning on stem cell genes in animals with mutant APC causes the mutant cells to multiply and produce tumors.
But when the study authors inactivated one copy of the mouse HMGA1 gene, there were fewer tumors and the mice survived longer. Mice with just one copy of HMGA1 can have normal lifespans.
“We were encouraged by this result because it suggests that if we could block HMGA1’s function by only 50%, we could significantly impact tumor development with no detrimental health effects on the mice,” Resar said.
The findings were published this month in the Journal of Clinical Investigation — and the work continues.
“Now that we know that HMGA1 is driving colon tumor development, the million-dollar question is how can we block it in therapy?” Resar mused. “We are very interested in developing therapies to block HMGA1 and to stimulate an immune system attack on the tumors.”
Resar is also exploring the role of HMGA1 in blood and pancreatic cancers since they also have elevated HMGA1 levels.
“Our findings are likely to be relevant not only to colon tumors but a broad spectrum of human cancers,” she said.
