| Autor: |
Nacarelli T; Glaxosmithkline, Oncology Synthetic Lethal Research Unit, Collegeville, PA 19426., Azar A; Merck, West Point, PA 19486., Potnis M; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102., Johannes G; Absorption Systems LLC, Exton, PA 19341., Mell J; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129., Johnson FB; Department of Pathology, University of Pennsylvania, Philadelphia, PA 19104., Brown-Borg H; Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58203., Noguchi E; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102., Sell C; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102. |
| Abstrakt: |
Cellular senescence is a terminal cell fate characterized by growth arrest and a metabolically active state characterized by high glycolytic activity. Human fibroblasts were placed in a unique metabolic state using a combination of methionine restriction (MetR) and rapamycin (Rapa). This combination induced a metabolic reprogramming that prevented the glycolytic shift associated with senescence. Surprisingly, cells treated in this manner did not undergo senescence but continued to divide at a slow rate even at high passage, in contrast with either Rapa treatment or MetR, both of which extended life span but eventually resulted in growth arrest. Transcriptome-wide analysis revealed a coordinated regulation of metabolic enzymes related to one-carbon metabolism including three methyltransferase enzymes (KMT2D, SETD1B, and ASH1L), key enzymes for both carnitine synthesis and histone modification. These enzymes appear to be involved in both the metabolic phenotype of senescent cells and the chromatin changes required for establishing the senescence arrest. Targeting one of these enzymes, ASH1L, produced both a glycolytic shift and senescence, providing proof of concept. These findings reveal a mechanistic link between a major metabolic hallmark of senescence and nuclear events required for senescence. |
