Abstract

The role of cellular metabolites in the direct control of signaling is an emerging and rapidly evolving field. Herein, we identify a key role for nuclear glycogen in epigenetic regulation through compartmentalized acetyl CoA production and histone acetylation. Nuclear glycogenolysis is dependent on ubiquitination and translocation of glycogen phosphorylase (GP) into the nucleus by malin, an E3 ubiquitin ligase. We developed an innovative in organello stable isotope tracer method coupled to mass spectrometry analysis to define the metabolic fate of nuclear glycogen. This work revealed that GP is required for nuclear glycogen degradation and subsequent glycolysis to generate substrates for histone acetylation. Inhibition of nuclear glycogenolysis is found to be particularly important in non-small cell lung cancer (NSCLC), as evident by increased nuclear glycogen accumulation and malin suppression in NSCLC. Re-introduction of malin in model NSCLC cell lines restores nuclear glycogenolysis, resulting in increased histone acetylation and transcriptional changes that delay cancer cell growth in vivo. This study uncovers a previously unknown role for glycogen metabolism in the nucleus and elucidates another way by which cellular metabolites control epigenetic regulation.