Researchers at Karolinska Institutet have unveiled a significant discovery regarding how cells modify their gene activity to survive in low-oxygen environments. The study, published in Nature Cell Biology on October 16, 2025, highlights a previously unknown mechanism that cells utilize to regulate protein production when oxygen levels drop, such as in tumors or following injuries.
The research team investigated the molecular adaptations of both breast cancer cells and human stem cells. They found that cells can alter the starting point for reading genes, which directly impacts the efficiency of protein synthesis. According to Kathleen Watt, a postdoctoral researcher at the Department of Oncology-Pathology and lead author of the study, “We saw that cells under hypoxia often use alternative start sites to regulate genes, which changes the characteristics of so-called 5′UTR sequence of mRNA.” This sequence serves as a preparatory stage before the protein formation begins and is crucial for how effectively proteins are produced.
As the study indicates, cells under low oxygen conditions frequently select different variants of the 5′UTR, allowing for more efficient production of essential proteins. Notably, the enzyme PDK1 was highlighted for its role in enabling cells to switch from oxygen-dependent energy production to glycolysis, a vital adaptation in stressful situations.
The researchers also identified that this switch is driven by epigenetic changes—chemical modifications that impact how DNA is packaged and which genes remain active. A specific modification known as H3K4me3 emerged as particularly significant. By manipulating this modification through pharmacological means, the researchers discovered they could prompt cells to change their gene start sites without altering oxygen levels. “This suggests that epigenetic changes are not just a consequence of hypoxia, but an active part of the cell’s adaptation strategy,” said Krzysztof Szkop, another postdoctoral researcher involved in the study.
These findings shed light on the ways cells manage protein production under stress, which could have far-reaching implications for cancer research, especially given that tumor cells often exist in low-oxygen surroundings. Ola Larsson, principal researcher at the Department of Oncology-Pathology and co-corresponding author of the study, remarked, “This study is the result of a fantastic collaborative effort between our group here at Karolinska Institutet and the group of Dr. Lynne-Marie Postovit at Queen’s University, along with our other colleagues in Canada.”
This research not only enhances our understanding of cellular resilience but also opens avenues for developing therapeutic strategies targeting how cancer cells adapt to hypoxic conditions. The implications of these findings could lead to novel approaches in treating various forms of cancer, emphasizing the crucial role of epigenetic mechanisms in cell survival.
