Mutations found in about 20% of human cancers may promote malignant growth through a shared change in how DNA is organized, according to research led by Weill Cornell Medicine investigators.
The study, published Oct. 28 in Nature, identifies a gene-regulating protein called CTCF and two partner protein complexes as possible targets for future cancer treatments. The findings come from laboratory and animal experiments, supported by analyses of patient data.
Researchers focused on the BAF complex, a group of proteins that helps regulate gene activity inside a cell’s nucleus. Mutations affecting its components occur in cancers as different as lymphoma, breast cancer, ovarian cancer and liver cancer.
Scientists have studied those mutations in individual tissues for years. The new work sought an explanation that could connect their effects across different types of cells and tumors.
A change in access to DNA
The BAF complex has multiple components encoded by more than two dozen human genes. It helps control access to DNA, which is wrapped, looped and folded inside the nucleus rather than arranged as a straight strand.
Using several animal and cell models, the investigators found that losing BAF function opened many sites across the genome to CTCF. The protein normally helps establish boundaries between DNA neighborhoods, influencing which genes can interact with the elements that regulate them.
When BAF function was lost, CTCF attached at thousands of additional sites. That changed DNA’s three-dimensional loops and folds, disrupted normal contacts between genes and their regulatory elements, and shifted gene activity toward faster cell division.
The result ran against the investigators’ initial expectation. Because BAF normally helps make DNA accessible, they expected its loss to reduce access. Instead, access increased specifically for CTCF, with effects extending across the genome, co-corresponding author Cem Meydan said.
The team tested BAF disruption through a chemical inhibitor and changes to the ARID1A gene. The initial experiments included 15 human cell lines and six genetically related cell lines with different levels of ARID1A function. Additional experiments examined mouse cells and tissues.
Reversing the growth-related changes
Deleting CTCF reversed the growth-related effects of BAF loss in an animal model. Analyses of mouse models and human patient data also supported CTCF’s role in cancers with BAF mutations, according to the investigators.
In the patient data, disruptions affecting CTCF were associated with better outcomes. Those observations complement the experimental findings; the study did not test a new treatment in patients.
The researchers also identified two other protein complexes, PBAF and ISWI, as CTCF partners. Removing those complexes blocked effects of BAF mutations, pointing to additional routes that scientists could investigate for treatment development.
The paper describes BAF loss as favoring shorter-range DNA contacts at the expense of longer-range interactions. It also reports that some cell types did not show significant changes, indicating that the response depends in part on cellular context.
Darko Barisic, an assistant professor of cancer biology in medicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, said the findings identify a possible common mechanism for one of the most frequent classes of cancer mutations.
Potential targets for further research
CTCF, PBAF and ISWI are candidates for future therapies in cancers carrying BAF mutations, rather than treatments established by this study. Barisic said his team is continuing to investigate how the increased CTCF binding changes the genome and hopes to identify a drug that blocks the process.
Barisic’s co-corresponding authors were Meydan, an assistant professor of research in systems and computational biomedicine at Weill Cornell Medicine, and Dr. Ari Melnick, director of the Josep Carreras Leukaemia Research Institute in Barcelona.
Meydan and postdoctoral research associates Sonia Debek and Christopher Chin were the study’s first authors. Investigators at Memorial Sloan Kettering Cancer Center and The Rockefeller University also collaborated.
Support came in part from three National Institutes of Health agencies: the National Cancer Institute, the National Institute of General Medical Sciences, and the National Institute of Neurological Disorders and Stroke.
Other supporters included the Leukemia Research Foundation, the Andrew McDonough B+ Foundation, LLS, the STARR Foundation, the Rita Allen Foundation, the Irma T. Hirschl/Monique Weill-Caulier Trust, the Simons Foundation and the Tri-Institutional Stem Cell Initiative.
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