Biology subjects

Sun, R. C.

Publications and source records attributed to Sun, R. C..

22 records · Page 2Linked to original sources

bioRxiv2020

Enhancing lifespan of budding yeast by pharmacological lowering of amino acid pools

The increasing prevalence of age-related diseases and resulting healthcare insecurity and emotional burden require novel treatment approaches. Several promising strategies seek to limit nutrients and promote healthy aging. Unfortunately, the human desire to consume food means this strategy is not practical for most people but pharmacological approaches might be a viable alternative. We previously showed that myriocin, which impairs sphingolipid synthesis, increases lifespan in Saccharomyces cerevisiae by modulating signaling pathways including the target of rapamycin complex 1 (TORC1). Since TORC1 senses cellular amino acids, we analyses amino acid pools and identified 17 that are lowered by myriocin treatment. Studying the methionine transporter, Mup1, we found that newly synthesized Mup1 traffics to the plasma membrane and is stable for several hours but is inactive in drug-treated cells. Activity can be restored by adding phytosphingosine to culture medium thereby bypassing drug inhibition, thus confirming a sphingolipid requirement for Mup1 activity. Importantly, genetic analysis of myriocin-induced longevity revealed a requirement for the Gtr1/2 (mammalian Rags) and Vps34-Pib2 amino acid sensing pathways upstream of TORC1, consistent with a mechanism of action involving decreased amino acid availability. These studies demonstrate the feasibility of pharmacologically inducing a state resembling amino acid restriction to promote healthy aging.

cell biology↗

bioRxiv2020

Mass Spectrometry Imaging of N-Glycans Reveals Racial Discrepancies in Low Grade Prostate Tumors

Prostate cancer is the most common cancer in men worldwide. Despite its prevalence, there is a critical knowledge gap regarding the underlining molecular events that result in higher incidence and mortality rate in Black men. Identifying molecular features that separate racial disparities is a critical step in prostate cancer research that could lead to predictive biomarkers and personalized therapy. N-linked glycosylation is a co-translational event during protein folding that modulates a myriad of cellular processes. Recently, aberrant N-linked glycosylation has been reported in prostate cancers. However, the full clinical implications of dysregulated glycosylation in prostate cancer has yet to be explored. Herein, we performed high-throughput matrix-assisted laser desorption ionization mass spectrometry analysis to characterize the N-glycan profile from tissue microarrays of over 100 patient tumors with over 10 years of follow up data. We identified several species of N-glycans that were profoundly different between low grade prostate tumors resected from White and Black patients. Further, these glycans predict opposing overall survival between White and Black patients with prostate cancer. These data suggest differential N-linked glycosylation underline the racial disparity of prostate cancer prognosis. Our study highlights the potential applications of MALDI-MSI for digital pathology and biomarker to study racial disparity of prostate cancer patients. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/260026v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@15f9b35org.highwire.dtl.DTLVardef@1c6d200org.highwire.dtl.DTLVardef@5188eorg.highwire.dtl.DTLVardef@8f347e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

Compartmentalized glycogenolysis regulates lung cancer transcription

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.

cancer biology↗

bioRxiv2019

Gas-chromatography coupled mass spectrometry for rapid and sensitive quantitation of glucose and glucose phosphates derived from glycogen

Glycogen is the primary storage carbohydrate in mammals and it is synthesized in most tissues. Glycogen contains covalently attached phosphate groups on hydroxyls of glucose units. The addition of phosphate modulates branching pattern, granular size, and crystallinity of a glycogen molecule, which all impact its accessibility to glycogen interacting enzymes during catabolism. As glycogen architecture modulates its role in metabolism, it is essential to accurately evaluate and quantify phosphate content in glycogen. Simultaneous quantitation of glucose and its phosphate esters is challenging and requires an assay with high sensitivity and a robust dynamic range. Currently, this method is lacking in the field. Herein, we describe a highly-sensitive method for the detection of both glycogen-derived glucose and glucose-phosphate esters utilizing gas-chromatography coupled mass spectrometry. Using this method, we observed higher glycogen levels in the liver compared to skeletal muscle, but skeletal muscle contained much more phosphate esters. These results confirm previous findings and establish the validity of the method. Importantly, this method can detect femtomole levels of glucose and glucose phosphate esters within an extremely robust dynamic range with excellent accuracy and reproducibility. The method can also be easily adapted for the quantification of glucose from plant starch, amylopectin or other biopolymers as well as covalently attached phosphate within them.

biochemistry↗