Scientists identify epigenetic key that ‘opens’ door to colon cancer microbiologystudy

A gene called high mobility group A1 (HMGA1) may be the key that opens the door to the development of colon cancer, according to research led by investigators from the Johns Hopkins Kimmel Cancer Center, Johns Hopkins Department of Medicine, Johns Hopkins Department of Pathology and the Johns Hopkins Institute for Cell Engineering.

The study, published in the Journal of Clinical Investigation, may provide a missing piece to explain why gut microbiome changes have been linked to rising rates of colon cancer in the United States, particularly in younger people.

Previous studies found high levels of HMGA1 gene expression in tumors of patients with colon cancer, but scientists did not know what role HMGA1 might be playing in this condition. Linda Resar, M.D., professor of medicine, pathology and oncology at the Johns Hopkins Kimmel Cancer Center, and her colleagues demonstrated that HMGA1 helps to switch on a network of tumor-promoting genes in mice that harbor a mutation in the adenomatous polyposis coli (mouse APC) gene. The APC gene was discovered by Kimmel Cancer Center researchers in 1991, and mutations in APC occur in over 90% of all colorectal tumors.

“HMGA1 functions like a molecular ‘key’ that ‘opens’ regions of the genome to activate stem cell genes in mutant colon cells, which in turn drives tumor development and progression,” Resar explains.

“The gene codes for the HMGA1 protein, a so-called ‘epigenetic regulator,’ which means that it modulates the structure of our genome, opening or closing different zones to activate or repress genes. Epigenetic regulators alter gene expression in response to many different factors, such as mutations, growth factor signals, inflammation, infection and other environmental cues.”

Chronic gut inflammation caused by modern diets high in ultra-processed foods has been linked with a higher risk of developing colon cancer and may help explain why more young people are developing this disease. To identify the early steps that lead from gut inflammation to colon cancer, Resar and her team studied two mouse models with Apc mutations, the most common colon cancer-linked mutation in humans.

Developed by co-author Cynthia Sears, M.D., the Bloomberg~Kimmel Professor of Immunotherapy, professor of medicine and oncology at the Johns Hopkins University School of Medicine, and professor of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health, the first mouse model has one copy of mutant Apc and a gut filled with an inflammatory bacterium that is found in people with colon cancer. These mice provide a unique system to study potential genetic-environmental interactions.

Another mouse model, developed by co-author Eric Fearon, M.D., Ph.D., director of the University of Michigan Rogel Cancer Center, has two copies of the mutant Apc, providing a potential model for colon cancer driven strictly by genetic factors.

Usually, both mouse models develop robust colon tumors. However, when Resar and her colleagues knocked out just one copy of the mouse HMGA1 gene, fewer tumors developed, and the mice survived longer. “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,” she says. In fact, mice with only one copy of HMGA1 have normal lifespans.

Next, they used single-cell genetic sequencing to try to determine why reducing HMGA1 had anti-tumor effects. They found that HMGA1 turned on the expression of genes normally active in colon stem cells, which led to an expansion in the mutant colon stem cells and tumor development.

Colon stem cells are normally responsible for repairing and completely replacing the lining of the human colon, a process that happens every few days and is essential for life. However, turning on stem cell genes in animals with mutant Apc caused the mutant cells to multiply and generate tumors. Preliminary results also suggest that high levels of HMGA1 may allow mutant tumor cells to escape detection by immune cells and prevent an anti-tumor immune response, although further studies are needed to confirm this.

Using a new technology called assay for transposase-accessible chromatin with sequencing (ATAC-seq), which allows scientists to examine “open” and “closed” regions of the genome, Resar and her team found that HMGA1 acts by “opening up” sections of the genome that are usually tucked away.

“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,” Resar says. One of the genes turned on by HMGA1 is ASCL2, a gene that was linked to early-onset colon cancer in another study. “That was particularly interesting because it might help to explain why we are seeing more colon cancer in younger people,” she explains.

The team confirmed that their findings were also relevant to human colon cancer when they looked at samples from patients with colon cancer and found high levels of HMGA1 and most of the stem cell genes active in the mouse models.

“Now that we know that HMGA1 is driving colon tumor development, the million-dollar question is how can we block it in therapy?” Resar says. “We are very interested in developing therapies to block HMGA1 and to stimulate an immune system attack on the tumors.”

She and her colleagues are currently testing ways to block HMGA1 and the stem cell genes it turns on as a potential strategy to treat colon cancer. They are also studying the role of HMGA1 in other cancers, including blood and pancreatic cancers, which 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 says.