Oglcnacylation regulates breast cancer metastasis via sirt1 modulation of foxm1 pathway christina m. Advances in functional genetic screens with transposons and crisprcas9 to illuminate cancer biology. Nacetylglucosamine oglcnac is an intracellular carbohydrate that dynamically modifies the amino acids serine and threonine through their hydroxyl moieties on nuclear and cytoplasmic proteins. Oglcnac is added by the enzyme ogt to serine and threonine of target proteins in the cytoplasm, nucleus, and mitochondrion 27, 28. This aberrant oglcnacylation correlates with augmented tumor cell proliferation and survival, increased tumor formation, invasion, metastasis, and resistance to therapy. The enzymes that catalyze the addition and removal of oglcnac have been cloned and characterized. Dnacetylglucosamine glcnac moieties to serinethreonine residues in target proteins is a frequently occurring posttranslational modification affecting the functionality of many cellular systems. Oglcnac and the epigenetic regulation of gene expression. Mechanistically, reducing oglcnac levels in breast cancer cells led to g1 cell cycle arrest and increased proteasomal degradation of the oncogenic transcription factor foxm1, causing a decrease in multiple foxm1specific targets, including sphase kinaseassociated protein 2, and a concomitant increase in cyclindependent kinase inhibitor p27. Oglcnacylation of the human epidermal growth factor. Townson 1department of molecular cellular and biomedical sciences, university of new hampshire, new hampshire, durham, nh, usa. Functional roles of oglcnac in cell signaling yonsei. The biology of cancer is a textbook for undergraduate and graduate biology students as well as medical students studying the molecular and cellular bases of cancer.
Oglcnacylation levels are found elevated in nearly all cancers examined. Oglcnac was termed a nutritional sensor, as global levels of the. Cancer metabolism and elevated oglcnac in oncogenic signaling. Novel cytoplasmic glycosylation of proteins in signal transduction. Reginato1,5 1department of biochemistry and molecular biology, drexel university college of medicine, philadelphia, pa 19102, usa. Oglcnac modification of sox2 regulates selfrenewal in pancreatic. The encyclopedia of cell biology offers a broad overview of cell biology, offering reputable, foundational content for researchers and students across the biological and medical sciences. Oglcnacylation is a dynamic posttranslational modification involved in a wide range of biological processes and diseases such as cancer.
Cervical cancer is the leading cause of cancerrelated death in women worldwide. Oglcnac in cancer cell biology o glcnacylation is catalysed by a single enzyme, termed o linked n acetylglucosamine transferase ogt, which transfers n acetylglucosamine from uridine diphosphate n acetylglucosamine udpglcnac to protein substrates 7. A single pair of enzymes o glcnac transferase ogt and o glcnacase. O glcnac is found on each of the core histones with sites mapped to h2a thr101, h2b ser36 and h4 ser47 ref. O glcnacylation and phosphorylation are two posttranslational modifications that antagonistically regulate protein function. The book presents the principles of cancer biology in an organized, cogent, and indepth manner. Both h2b ser36 and h4 ser47 are found on the lateral surface of the nucleosome and contact the dna either directly in the case of h2b ser36 or indirectly in the case of h4 ser47 46.
Immunoblotting analysis using the oglcnacspecific antibodies has indicated that glucose deprivation increases protein oglcnacylation in some cancer cells. Regulation of jakstat signalling in the immune system. Oglcnac signaling in cancer metabolism and epigenetics. Oglcnacylation of proteins for effective use of sugar under stress and deprivation conditions is one of the adaptive responses of the cancerous cells and further research is needed to. Circulating exosomes for early diagnosis of pancreatic cancer. The tmas were quantitated independently and blindly by 3 research. A better understanding of oglcnac signaling in cancer initiation, progression and metastasis would help to identify new targets that can be used for diagnosis, prevention, and treatment of human cancer. Understanding how this altered metabolism is regulated has recently emerged as an intense research focus in cancer biology. Oglcnac, an essential regulator of numerous cellular pathways. Oglcnac is essential for cell survival and plays important role in many biological processes e. The results of recent studies suggest that oglcnacylation, which involves the addition of nacetylglucosamine on the serine or threonine residues of proteins, may play a. Analogous to phosphorylation, oglcnacylation plays crucial regulatory roles in a variety of cellular processes.
Oglcnacylation enhances the tumorigenic properties of cervical cancer cells in vitro nicole m. Nacetylglucosamine oglcnac moiety linked to the serine or threonine residues in proteins. Oglcnac was termed a nutritional sensor, as global levels of the modification are elevated in response to increased glucose and glutamine flux into the hexosamine biosynthetic pathway. As a form of protein glycosylation, it differs from most other forms in three aspects. This book chapter describes nonradioactive colorimetric assays for glycosyltransferases and sulfotransferases. Ogt is involved in the resistance of insulin in muscle cells and adipocytes by inhibiting the threonine 308 phosphorylation of akt1, increasing the rate of irs1 phosphorylation at serine 307 and serine 632635, reducing insulin signaling, and. Roles of regulatory posttranslational modifications, in particular oglycosylation, in increasing functional diversity of proteins. Inhibition of oglcnac transferase activity reprograms. This neuroprotection could possibly be explained with a reduction in nmdastimulated calcium mineral influx following the administration of hu210, discovered specifically in ethanolwithdrawn neurons. Increased total oglcnacylation is emerging as a general characteristic of cancer cells, and recent studies suggest that oglcnacylation is a central. Ab many nuclear and cytosolic proteins are modified with olinked. A conserved splicing silencer dynamically regulates oglcnac transferase intron retention and o. Natasha zachara on oglcnac, an essential regulator of numerous cellular pathways, part of a collection of online lectures.
Dnacetylglucosamine glcnac sugars to serine or threonine residues of nuclear and cytoplasmic proteins, and it is involved in extensive crosstalk with other posttranslational modifications, such as phosphorylation. Oglcnacylation regulates breast cancer metastasis via. Since many of these cancers also had increased ogt rna and protein levels, it is not clear whether elevated oglcnacylation is due to increased. Mechanistic insights of oglcnacylation that promote progression of cholangiocarcinoma cells via nuclear translocation of nf.
This book aims to promote more research for improved understanding of protein glycosylation and its application to commercial products. Book chapters are listed at the bottom of this page. Glycosylation is also present in the cytoplasm and nucleus as the oglcnac modification. The single mammalian ogt gene is located on the human x chromosome near the xist locus and encodes multiple alternatively spliced isoforms of ogt targeted to these different intracellular. Thus, manipulation of oglcnac levels using chemical or shrnamediated inhibition of oga or ogt affects in vitro and in vivo migrationinvasion of breast 31, 112, 121, lung 31, 33, liver, prostate, and colon cancer cells.
Detecting oglcnac using in vitro sulfation this publication describes a method for oglcnac detection using in vitro sulfation using the two glcnac sulfotransferases carbohydrate sulfotransferase chst 2 and chst4 and the. In this report we present experimental evidence suggesting that the epidermal growth factor receptor egfr is. Aglycosylation is a feature of engineered antibodies to bypass glycosylation. Oglcnac transferase regulates cancer stemlike potential of.
The potential role of oglcnac modification in cancer. Inhibition of oglcnac transferase activity reprograms prostate cancer cell metabolism harri m. In cancer, it was observed that the biosynthesis of ogalnac glycans is often abnormal, which may affect the biology and survival of the cancer cell. Identification of novel proteins differentially expressed in pluripotent. O glcnacylation is a nutrient and stressresponsive posttranslational modification ptm that involves the attachment of o linked n acetylglucosamine moieties to ser and thr residues of cytoplasmic, nuclear and mitochondrial proteins. Knockdown of ogt reduces cancer cell hyperoglcnacylation and inhibits. Detecting oglcnac using in vitro sulfation glycobiology. This chapter presents an overview of the function of oglcnac modification in various signaling pathways. One of the remarkable features of cancer cells is aerobic glycolysis, a phenomenon also known as the warburg effect 18 20, in which cancer cells rely preferentially on glycolysis instead of oxidative phosphorylation as the main energy source even in the presence of high oxygen tension. Park sk, zhou x, pendleton k, hunter ov, kohler jj, odonnell ka, conrad nk 2017. This important work includes 285 articles from domain experts covering every aspect of cell biology, with fully annotated figures, abundant illustrations. Thus, understanding the regulation of oglcnacylation in tumor cells and their. A number of labs have seen similar reduction in tumor cell growth when ogt or oglcnacylation is reduced. Cessation of chronic ethanol usage can raise the level of sensitivity of the mind to excitotoxic problems.
Nacetylglucosamine oglcnac is a highly dynamic intracellular protein modification responsive to stress, hormones, nutrients, and cell cycle stage. Nacetylglucosamine oglcnac, which was discovered in the early 1980s, is the covalent addition of a glcnac sugar. This oglcnacylation is a dynamic posttranslational modification similar to phosphorylation. Jaskiewicz 1,2, crystal hermawan1, stephanie parisi1 and david h. Nacetylglucosamine oglcnac at serine or threonine residues. Cancer cells exhibit increased uptake of glucose and glutamine, and rewire the metabolic flux toward anabolic pathways important for cell growth and proliferation. Diet and environmental factors can alter the scope of epigenetic regulation. Finally, oglycosylated glycoproteins may be important during reproduction and fertilization. Nacetylglucosaminylation oglcnacylation, has been discovered in many types of epithelial cancers, including those of the female reproductive tract, but the role it potentially plays in cellular growth and metastasis is unclear. Cancer metabolism and elevated o glcnac in oncogenic. Here we investigated the role of o glcnacylation during vernalization, a process whereby prolonged cold exposure promotes. Oglcnacylation enhances the tumorigenic properties of. Ogt, oglcnac, sox2, pancreatic cancer, metabolism, selfrenewal.
Chemical biology of glycoproteins by zhongping tan. We also discuss inhibition of hyperoglcnacylation as a potential novel. Distinguished research professor of biochemistry and molecular biology. Purchase glycosylation and cancer, volume 126 1st edition. Numerous studies indicate that oglcnac promotes cancer cell invasiveness and metastasis. Oglcnac, glucose deprivation and cancer antibody news. Oglcnacylation is becoming increasing realized as having important roles in cancerrelevant processes, such as. Similar to phosphorylation, olinked nacetylglucosamine oglcnac modification of nuclear and cytosolic proteins is an abundant, dynamic, and. There is no doubt that cancer is not only a genetic disease but that it can also occur due to epigenetic abnormalities. Nactylglucosamine oglcnac is a carbohydrate posttranslational modification on hydroxyl groups of serine andor threonine residues of cytosolic and nuclear proteins. Department of molecular biology and biochemistry and department of chemistry, simon fraser university, 8888 university dr, burnaby, bc, v5a 1s6, canada.
This novel mechanism where oglcnacylation regulates cancer cell metabolic reprograming via regulation of hif1. In addition, we identify klf8 as a novel regulator of breast cancer mammosphere formation and a critical target of ogt in regulating cancer. O glcnac transferase is a part of a host of biological functions within the human body. A unique feature of cancer cell energy metabolism is a shift from oxidative phosphorylation to the less efficient glycolytic pathway warburg effect, necessitating greatly increased glucose uptake. N2 olinked nacetylglucosamine oglcnac is a dynamic nutrient sensor that regulates nearly all aspects of cellular physiology see oglcnacylation. The clarity of writing and the lucid fullcolor art program make the book accessible and engaging. It appears that oglcnac is part of the histone code, regulating gene transcription in an epigenetic manner. A mitotic glcnacylationphosphorylation signaling complex. Alterations in oglcnac addition or removal cycling impair cell cycle progression and cytokinesis, but the mechanisms are not well understood. The potential role of oglcnac modification in cancer epigenetics the lectinbinding pattern of nucleolin and its interaction with endogenous galectin3 mir375 induces human decidua basalisderived stromal cells to become insulinproducing cells. However, the regulation of and the cross talk between these two protein modifications are poorly understood in plants. Taken together, oglcnac appears to be important in tumor biology, and altered oglcnacylation is an event found in many types of cancer. Circulating exosomes for early diagnosis of pancreatic cancer 1 reply the best way to cure cancer is to catch it early when surgical removal of a localized mass can successfully rid the patient of all cancer cells and cancer stem cells. Therefore, oglcnac signaling may play a central role in integrating metabolic and epigenetic reprogramming in cancer.