Tackling cancer with new insights into cellular processes
While every cell in the body contains the same DNA, they acquire different functions. This happens because distinct sets of genes are switched on or off, modifying DNA and their associated proteins without changing the genetic code itself. “Importantly, these epigenetic modifications are not static,” explains EPICAMENTE(opens in new window) project coordinator Sara Sdelci from the Centre for Genomic Regulation(opens in new window) in Spain. “They require a continuous supply of energy and chemical building blocks to be established, maintained and removed.” These building blocks are provided by cellular metabolism, the network of biochemical reactions that allows cells to generate energy and adapt to their environment. A key aim of the EPICAMENTE project was to understand how metabolic activity can directly influence gene regulation, rather than serving only as a general source of energy and metabolites.
Studying metabolism and gene regulation together
The project, supported by the European Research Council(opens in new window), brought together expertise in molecular biology, genomics, proteomics and chemical biology. Using large-scale proteomic approaches(opens in new window), the team was able to shine new light on how metabolic mechanisms contribute to fundamental cellular processes. “Rather than asking only whether a metabolic enzyme is important for a given process, we asked where its activity is required inside the cell,” says Sdelci. “This focus on subcellular localisation revealed regulatory mechanisms that remain hidden if metabolism is treated as a uniform cellular process.” Through this groundbreaking work, the project team was able to demonstrate that metabolism is directly integrated into genome regulation. “We showed that metabolic enzymes can directly regulate epigenetic modifications,” remarks Sdelci. “We also found that nuclear metabolic activity supports essential cellular processes such as cell division and DNA repair. Together, these findings redefine metabolism as an active regulatory layer of genome function rather than solely a provider of energy and biosynthetic precursors.”
How cancer cells exploit metabolic mechanisms
Importantly, the results also showed that cancer cells can activate or exploit specific nuclear metabolic mechanisms, particularly under conditions of stress. This highlights the biological relevance of these pathways in disease contexts, while also indicating that they are not exclusive to cancer cells. “This could provide the foundation for more selective therapeutic strategies in the future,” adds Sdelci. “Because metabolic enzymes can perform distinct functions depending on their cellular location, targeting specific gene regulatory roles rather than globally inhibiting metabolism may allow greater precision and reduced side effects.” Over the longer term, these insights could contribute to the development of improved biomarkers based on metabolic and epigenetic regulation, and to the design of strategies that integrate metabolic modulation with existing treatments.
Implications for development, ageing and disease
Certainly, the work carried out by EPICAMENTE has opened up new avenues of research, focused on understanding how metabolic activity within cells can influence biological outcomes. “More broadly, this work has established a conceptual framework for studying metabolism as a spatially organised regulatory system, with implications for development, ageing and disease,” notes Sdelci. Future work could involve identifying which metabolic activities are essential specifically at the level of the nucleus and determining how these activities are regulated during different cellular states such as stress. An important goal will be to understand how these mechanisms vary across cell types and physiological contexts.
