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How a researcher unraveled DNA from a histone spool and found the gene that enhances a cell to become colorectal cancer
Grantee: Kunal Rai, PhD
Funding: ACS-Lisa Dean Moseley Foundation
Institution: University of Texas MD Anderson Cancer Center in Houston
Area of Focus: Biochemistry and Immunology of Cancer
Grant Term: 10/01/2019 to 9/30/2023
“My lab focuses on understanding the contribution of the physical structure of DNA—called the epigenome—to the progression of cancer and on identifying new venues for therapy and diagnostic tools. Abnormal structures in the epigenome—or epimutations—have emerged to be a key feature associated with cancer progression. And although researchers hypothesize that these events could be exploited for personalized medicine, how to do that is not yet well understood.
“My lab has recently shown that the epigenetic content of tumors can be analyzed and used to stratify patients into groups based on epigenomic subtypes, identifying which patients will respond to specific targeted therapies in colorectal cancers.”–Kunal Rai, PhD
The Challenge: Colorectal cancer often starts as a non-cancerous (benign) polyp, which is a small growth from the inner lining of the colon that projects into its hollow center. These polyps, called adenomas, are considered a pre-cancerous condition. But over time the polyps can become cancerous (malignant) tumors, called adenocarcinomas.
The transformation to cancer is caused from changes (mutations) that occur in specific genes of a cell’s DNA. The complete set of DNA in a cell is the genome. The activity of the genome is managed by the epigenome, which is made of chemical compounds and proteins that attach to specific genes along DNA.
Scientists know which genes case adenocarcinomas, but they don’t understand what epigenetic changes (epimutations) start the cancer’s development. If they did, they’d have the first information needed to develop or improve a targeted therapy to treat these colorectal cancers.
The Research: ACS-Lisa Dean Moseley Foundation grantee Kunal Rai, PhD, and his lab team recently published a study about epigenetics and chromatin in relation to colorectal cancer. Chromatin is a tightly coiled form of DNA that is small enough to fit into the cell. DNA wraps around spool-like proteins called histones to provide structure for how DNA is coiled. Chemical groups added or removed from the epigenome influence how tightly DNA wraps around histones and affect whether a gene is “turned on” or “off.” For instance, tightly wrapped genes are unreadable, and relaxed genes are easily readable.
When epigenetic compounds attach to histones near a gene, they’re described as having modified or “marked” the genome for ‘reading.’ In a recently published study, Rai’s team identified a histone marker on a special gene called an ‘enhancer’ that seems to be a major epigenetic error involved in the development and growth of colorectal cancer.
Enhancers are genes that make it more likely that another gene—which the enhancer may not be close to—will be “turned on.” Loops in the chromatin bring the enhancer and the target gene close to each other, which is key to gene regulation.
Rai’s team identified tumor-specific enhancer genes that could be targeted to treat certain colorectal cancers. They tested drugs that slowed (inhibited) the specific enhancer genes on different adenocarcinoma types in mice. After that treatment, all the tumors were smaller.
Why it Matters: Rai’s work identified differences in gene-enhancer patterns between people with colorectal cancer. That means there’s potential for precision combination therapy in the future.
He is one of the first researcher to identify epigenetic subtypes of colorectal cancer. His findings present new, potential targeted therapeutic strategies for all of them.
Epigenetic treatments, also called epi-drugs, can reverse abnormal epigenetic modifications in cancer cells. Their main benefit is that they don’t kill all fast-growing cells, including hair cells, like some cancer treatments do. Instead, the goal of epi-drugs is to “reprogram” cancer cells by reversing the epimutation. That means less toxicity and potentially fewer side effects for patients being treated with a targeted epi-drug.