Exportin-1, a protein often found at high levels in leukemia and other cancers, was previously known for transporting materials out of a cell’s nucleus. New research shows it may also play a role in activating gene transcription. If this function is hijacked, it could promote uncontrolled cell division, contributing to cancer. Targeting Exportin-1’s role in transcription may lead to more effective and less toxic cancer therapies in the future.
The unexpected discovery may provide scientists with new insights into how cancer develops — and how to combat it.
Researchers at Northwestern University have discovered a previously unknown function of a protein called Exportin-1 (also known as Xpo1 or Crm1), which is found in the nuclei of all plant and animal cells. While Exportin-1 is already known for transporting materials out of the nucleus, the team found that it also plays a key role in enhancing gene transcription, the process by which DNA is copied into RNA to activate gene expression.
The study revealed that transcription factors, which regulate this process, can guide genes to the nuclear pore complex, the gateway that controls molecular traffic in and out of the nucleus. Exportin-1 acts as a bridge in this interaction. By anchoring transcription factors (and the genes they regulate) to nuclear pore proteins, Exportin-1 helps reposition genes to the edge of the nucleus. This relocation boosts transcription activity, leading to stronger gene expression.
Link to Cancer Development
“Because Exportin-1 is often overexpressed in cancers and leukemia, this work also raises the possibility that this newly discovered function is important in promoting cancer growth,” said Molecular Biosciences Professor Jason Brickner, who led the study. “The work provides a molecular explanation for a phenomenon I discovered 20 years ago — the movement of genes to the nuclear periphery when they are turned on.”
Brickner’s 20 years of research in the department of molecular biosciences at Northwestern’s Weinberg College of Arts & Sciences has mainly focused on yeast, an organism he says is “an excellent model for eukaryotic cells” because it has many features in its nucleus that are present universally across all plants, animals and fungi. Because Exportin-1 is found in all these organisms, the way it interacts with the genome may be true in all eukaryotes.
The interdisciplinary and cross-institutional team employed a variety of methods to untangle Exportin-1’s specific functions in budding yeast, including single molecule tracking, chromatin localization in live cells, genome-wide mapping, and biochemistry.
The unexpected findings, published in the journal Molecular Cell, could aid other scientists as they seek to develop new medications that stymie cancer growth without harming healthy cellular function.
Implications for Cancer Therapy
“Exportin-1 is overexpressed in many leukemias and cancers. Because it binds to the genome, it may alter transcription to promote oncogenesis,” said Northwestern Ph.D. student and first author Tiffany Ge. “Inhibitors of Exportin-1 are given to patients who fail to respond to first- or second-line chemotherapies. But these therapies are very toxic and have many side effects because they block all nuclear export, which is an essential function of cells.”
A renewed understanding of the protein’s dual role introduces the possibility that its overexpression promotes cancer development by enhancing the expression of genes responsible for cell division. Inhibiting just this process without impacting nuclear export could lead to the production of better medications. Whether Exportin-1’s role in transcription is also essential and would give medications a similarly toxic effect, however, has not yet been tested.
Before drug development is considered, the researchers hope to confirm that the interaction between transcription factors and Exportin-1 is generalizable across species, as well as better define the specifics of the molecular interaction.
Reference: “Exportin-1 functions as an adaptor for transcription factor-mediated docking of chromatin at the nuclear pore complex” by Tiffany Ge, Donna Garvey Brickner, Kara Zehr, D. Jake VanBelzen, Wenzhu Zhang, Christopher Caffalette, Gavin C. Moeller, Sara Ungerleider, Nikita Marcou, Alexis Jacob, Vu Q. Nguyen, Brian Chait, Michael P. Rout and Jason H. Brickner, 10 March 2025, Molecular Cell.
DOI: 10.1016/j.molcel.2025.02.013
The research was supported by the National Institutes of Health (grants R35 GM136419, P41 GM109824, R01 GM112108, T32 NIGMS GM008061 and F32 GM153164) and a predoctoral fellowship from the National Science Foundation.
