S6K1 phosphorylation, a potential new biomarker and therapeutic target for obesity

Dr. George Thomas, head of the Laboratory of Cancer Metabolism at the Bellvitge Biomedical Research Institute (IDIBELL) and the Catalan Institute of Oncology (ICO), and his close collaborator Dr. Sara Kozma have led a study which uncovered a novel role of S6K1 in the induction of an epigenetic network that plays a role in fat formation. The study, published in Molecular Cell, and highlighted in a Preview, was carried out in collaboration with researchers from Standford, Cincinnati and Korea, could potentially lead to the development of diagnostic biomarkers and targeted drugs for obesity, which has become a worldwide epidemic associated with a number of pathologies including diabetes, hyperlipidemia, cardiovascular disease, and cancer.

Previous studies by Drs. Thomas and Kozma had already shown that S6K1 plays a critical role in lipid production by transcriptionally regulating the differentiation of mesenchymal stem cells (MSCs) into adipocytes (fat cells), although the nuclear signaling pathways by which this response was mediated were not completely understood.

This new publication demonstrates that S6K1 transcription is mediated by the BMP4-induced translocation of S6K1 to the nucleus, histone H2B phosphorylation leading to the recruitment of EZH2 and histone H3 trimethylation. This epigenetic switch drives early adipogenesis (fat formation), which is the main cause of obesity. These results suggest that direct inhibitors of S6K1 may serve as a potential therapeutic route to suppress obesity, a possibility being explored now by the researchers.

The results of the study also suggest that S6K1-mediated phosphorylation correlates with Body Mass Index (BMI). Therefore, the level of phosphorylation could serve as a potential biomarker for obesity, given that hyperactivation of this signaling pathway has been seen in tissue samples from overweight individuals. Dr. Kozma started collaborating with Dr. José Manuel Fernández-Real, Principal Investigator of the CIBERobn research group in Girona, regarding this exciting possibility.

Link to the article

Image: Adipogenesis is mediated by translocation of S6K1 to the nucleus, histone H2B phosphorylation and histone H3 trimethylation.