SEOUL, September 07 (AJP) - How the genome is folded inside a cell can drive cancer without any change to the DNA sequence itself, and a review by two South Korean researchers argues that the folding should be treated as a target for cancer drugs.
The review appeared in June in Experimental & Molecular Medicine, a journal published by the Korean Society for Biochemistry and Molecular Biology. Its authors, Jang Sun-young and Yoo Kyung-hyun, work in the Laboratory of Biomedical Genomics at Sookmyung Women's University. The paper reports no new experiments. It surveys what the field has established about the shape of the genome in tumors and proposes what might be done with that knowledge.
The proposal rests partly on the same laboratory's earlier results. Working with liver cancer cells, the Sookmyung group reported in July last year in the journal Cancer Communications that an activated form of the protein STAT3 pulls distant stretches of DNA into new points of contact, switching on genes that drive invasion and the growth of blood vessels that feed a tumor. When STAT3 inhibitors were applied, the drug reached its target, but the rearranged structure stayed where it was.
A tumor whose architecture outlasts the drug can keep the same genes running. That is one reason a treatment can work on paper and fail in a patient.
Folding matters because there is so much DNA and so little room for it. A human cell carries roughly two meters of DNA inside a nucleus about six micrometers wide, less than a tenth the width of a human hair. The molecule is more than 300,000 times longer than the space that holds it, and the way it is packed determines which genes a cell can read.
That packing follows a rough order. At the largest scale the genome sorts itself into two broad territories, one where active genes cluster together and one where silenced regions do. Within those territories the DNA is divided into neighborhoods, called topologically associating domains, that behave something like walled blocks. A gene inside a block can be reached by the control switches inside the same block and is largely shielded from switches next door. Inside the blocks, the strand loops back on itself to bring particular switches into contact with particular genes.
Two proteins do much of the building. CCCTC-binding factor, usually written as CTCF, marks the boundaries, and a ring-shaped protein complex called cohesin draws the strand through itself to form the loops. When either is damaged or lost, walls come down.
What follows is the part that makes the folding a cancer problem. A broken boundary lets a control switch from one neighborhood reach a gene in the next, a process researchers call enhancer hijacking. Some of these switches are unusually powerful stretches of DNA known as super-enhancers, and when one of them is redirected onto a gene that promotes cell growth, the gene can be driven hard without a single letter of its sequence changing.
Seeing any of this required instruments that did not exist a generation ago. Hi-C, the technique that opened the field, chemically locks together pieces of DNA that are physically touching, then sequences them to build a map of which parts of the genome are in contact with which others. HiChIP narrows that map to contacts involving a particular protein. Single-cell methods apply the same logic one cell at a time, which matters in tumors, where no two cells are quite alike. Applied across tumor types, these tools have found spatial reorganization to be widespread rather than exceptional.
The review's therapeutic argument turns on plasticity. Structure, unlike a mutation, is not fixed. Boundaries that have collapsed in a cancer cell might be restored, and the review points to CRISPR-based tools that can already move or rebuild specific contacts in the laboratory.
A second proposed lever is phase separation, the tendency of certain proteins to gather into dense liquid droplets inside the nucleus, much as oil separates from water. Those droplets concentrate the machinery that switches genes on, and in some cancers they form where they should not. Dissolving or restraining them is one way the review suggests the architecture might be pushed back toward normal.
Jang, who took her undergraduate degree at Sookmyung and then completed a master's and doctorate there under Yoo's supervision, said understanding three-dimensional genome structure "explains the mechanism of cancer in a new way and will be an important foundation for patient-tailored precision medicine and the development of next-generation cancer treatments."
None of it has been tried as a treatment. Restoring a collapsed boundary and controlling phase separation are proposals, not results. CRISPR tools that edit genome architecture are laboratory instruments used on cells in a dish, and neither the review nor the work it draws on identifies a compound that could do the same thing in a person.
No drug designed to target the shape of the genome rather than its sequence has entered a clinical trial.
[Reference Information]
Journal/Source: Experimental & Molecular Medicine (IF=17.5, JCR 2.9%)
Title: 3D chromatin architecture in cancer: mechanisms of dysregulation and emerging therapeutic strategies
Link/DOI: https://bit.ly/4h0rVN0
AJP Takeaways
- Sookmyung Women's University researchers Jang Sun-young and Yoo Kyung-hyun argue in Experimental & Molecular Medicine that the folded shape of the genome inside a cell nucleus drives cancer independently of mutations in the DNA sequence, and that the folding itself should be treated as a drug target.
- The same laboratory reported in Cancer Communications in July last year that in liver cancer cells, structural rearrangements caused by the protein STAT3 persisted after STAT3 inhibitors were applied, a possible mechanism for why a targeted drug can reach its target and still fail.
- The June paper is a review rather than original research, and the strategies it proposes, restoring collapsed structural boundaries and controlling the formation of protein droplets in the nucleus, have not been tested as treatments in patients.
- No drug designed to target genome architecture rather than genetic sequence has entered a clinical trial.
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