Researchers at Karolinska Institutet have identified a mechanism that enables cells to adjust their gene activity in response to low oxygen levels, a discovery that could have significant implications for cancer research. The findings, published in Nature Cell Biology on October 16, 2025, reveal how cells switch their protein production processes to survive in oxygen-deprived environments such as tumors or after injuries.
The study delves into the molecular adaptations that occur when cells experience hypoxia, a condition characterized by inadequate oxygen supply. By examining both breast cancer cells and human stem cells, the researchers uncovered that cells utilize alternative starting points for gene expression. This adjustment impacts the efficiency of protein synthesis, crucial for cellular survival under stress.
Kathleen Watt, a postdoctoral researcher at the Department of Oncology-Pathology at Karolinska Institutet and the study’s lead author, explained, “We saw that cells under hypoxia often use alternative start sites to regulate genes, which changes the characteristics of the so-called 5′UTR sequence of mRNA.” This sequence serves as a preliminary segment before the actual protein is synthesized, with its properties influencing how effectively proteins are produced.
The research highlights that, during low oxygen conditions, cells frequently opt for different variants of 5′UTRs. This choice allows the efficient production of critical proteins, such as the enzyme PDK1. This enzyme plays a pivotal role in shifting cellular energy production from an oxygen-dependent process to one that can proceed anaerobically, known as glycolysis—a vital adaptation mechanism for cells in challenging environments.
The study also emphasizes that these cellular switches are regulated by epigenetic modifications, specifically chemical alterations in DNA packaging that influence gene activity. One significant modification identified was H3K4me3, which the researchers found to be crucial in the process. By manipulating this modification through pharmacological means, they demonstrated that cells can alter their gene start sites without changes in oxygen levels.
Krzysztof Szkop, another postdoctoral researcher involved in the study, noted, “This suggests that epigenetic changes are not just a consequence of hypoxia, but an active part of the cell’s adaptation strategy.” This insight may pave the way for new therapeutic approaches in cancer treatment, as tumor cells often exist in low-oxygen environments.
The collaboration between Karolinska Institutet and the team led by Dr. Lynne-Marie Postovit at Queen’s University in Canada was instrumental in achieving these findings. Ola Larsson, the principal investigator and co-corresponding author of the study, remarked on the collaborative effort: “This study is the result of a fantastic collaborative effort between our group here at Karolinska Institutet and our colleagues in Canada.”
The research underscores the complex interplay between epigenetic changes and cellular adaptation mechanisms under stress, contributing to a deeper understanding of how cells navigate survival in adverse conditions. These findings could have far-reaching implications, particularly in the context of cancer research, where understanding cellular responses to low oxygen could inform the development of novel treatments.
