bims-meprid 2021-12-12 papers

Front Immunol. 2021 ;12 772304

O-GlcNAcylation in Chronic Lymphocytic Leukemia and Other Blood Cancers.

In the past decade, aberrant O-GlcNAcylation has emerged as a new hallmark of cancer. O-GlcNAcylation is a post-translational modification that results when the amino-sugar β-D-N-acetylglucosamine (GlcNAc) is made in the hexosamine biosynthesis pathway (HBP) and covalently attached to serine and threonine residues in intracellular proteins by the glycosyltransferase O-GlcNAc transferase (OGT). O-GlcNAc moieties reflect the metabolic state of a cell and are removed by O-GlcNAcase (OGA). O-GlcNAcylation affects signaling pathways and protein expression by cross-talk with kinases and proteasomes and changes gene expression by altering protein interactions, localization, and complex formation. The HBP and O-GlcNAcylation are also recognized to mediate survival of cells in harsh conditions. Consequently, O-GlcNAcylation can affect many of the cellular processes that are relevant for cancer and is generally thought to promote tumor growth, disease progression, and immune escape. However, recent studies suggest a more nuanced view with O-GlcNAcylation acting as a tumor promoter or suppressor depending on the stage of disease or the genetic abnormalities, proliferative status, and state of the p53 axis in the cancer cell. Clinically relevant HBP and OGA inhibitors are already available and OGT inhibitors are in development to modulate O-GlcNAcylation as a potentially novel cancer treatment. Here recent studies that implicate O-GlcNAcylation in oncogenic properties of blood cancers are reviewed, focusing on chronic lymphocytic leukemia and effects on signal transduction and stress resistance in the cancer microenvironment. Therapeutic strategies for targeting the HBP and O-GlcNAcylation are also discussed.

Keywords: O-GlcNAc transferase (OGT); O-GlcNAcase (OGase); O-linked β-D-N-acetylglucosamine (O-GlcNAc); cancer; chronic lymphocytic leukemia; cytokines; metabolism; signal transduction

DOI: https://doi.org/10.3389/fimmu.2021.772304

Trends Plant Sci. 2021 Dec 02. pii: S1360-1385(21)00284-3. [Epub ahead of print]

Dynamic epigenetic modifications in plant sugar signal transduction.

Qingshuai Chen, Jing Zhang, Gang Li.

In eukaryotes, dynamic chromatin states are closely related to changes in gene expression. Epigenetic modifications help plants adapt to their ever-changing environment by modulating gene expression via covalent modification at specific sites on DNA or histones. Sugars provide energy, but also function as signaling molecules to control plant growth and development. Various epigenetic modifications participate in sensing and transmitting sugar signals. Here we summarize recent progress in uncovering the epigenetic mechanisms involved in sugar signal transduction, including histone acetylation and deacetylation, histone methylation and demethylation, and DNA methylation. We also highlight changes in chromatin marks when crosstalk occurs between sugar signaling and the light, temperature, and phytohormone signaling pathways, and describe potential questions and approaches for future research.

Keywords: DNA methylation; epigenetics; gene expression; histone modification; sugar signal

DOI: https://doi.org/10.1016/j.tplants.2021.10.009

Int J Mol Sci. 2021 Dec 02. pii: 13057. [Epub ahead of print]22(23):

Emerging Role of TCA Cycle-Related Enzymes in Human Diseases.

Woojin Kang, Miki Suzuki, Takako Saito, Kenji Miyado.

The tricarboxylic acid (TCA) cycle is the main source of cellular energy and participates in many metabolic pathways in cells. Recent reports indicate that dysfunction of TCA cycle-related enzymes causes human diseases, such as neurometabolic disorders and tumors, have attracted increasing interest in their unexplained roles. The diseases which develop as a consequence of loss or dysfunction of TCA cycle-related enzymes are distinct, suggesting that each enzyme has a unique function. This review aims to provide a comprehensive overview of the relationship between each TCA cycle-related enzyme and human diseases. We also discuss their functions in the context of both mitochondrial and extra-mitochondrial (or cytoplasmic) enzymes.

Keywords: TCA cycle; TCA cycle-related enzymes; calcium oscillations; human diseases; mitochondria

DOI: https://doi.org/10.3390/ijms222313057

Int J Mol Sci. 2021 Dec 04. pii: 13129. [Epub ahead of print]22(23):

Acetyl-CoA Carboxylase Inhibitor CP640.186 Increases Tubulin Acetylation and Impairs Thrombin-Induced Platelet Aggregation.

Marie Octave, Laurence Pirotton, Audrey Ginion, Valentine Robaux, Sophie Lepropre, Jérôme Ambroise, Caroline Bouzin, Bruno Guigas, Martin Giera, Marc Foretz, Luc Bertrand, Christophe Beauloye, Sandrine Horman.

Acetyl-CoA carboxylase (ACC) is the first enzyme regulating de novo lipid synthesis via the carboxylation of acetyl-CoA into malonyl-CoA. The inhibition of its activity decreases lipogenesis and, in parallel, increases the acetyl-CoA content, which serves as a substrate for protein acetylation. Several findings support a role for acetylation signaling in coordinating signaling systems that drive platelet cytoskeletal changes and aggregation. Therefore, we investigated the impact of ACC inhibition on tubulin acetylation and platelet functions. Human platelets were incubated 2 h with CP640.186, a pharmacological ACC inhibitor, prior to thrombin stimulation. We have herein demonstrated that CP640.186 treatment does not affect overall platelet lipid content, yet it is associated with increased tubulin acetylation levels, both at the basal state and after thrombin stimulation. This resulted in impaired platelet aggregation. Similar results were obtained using human platelets that were pretreated with tubacin, an inhibitor of tubulin deacetylase HDAC6. In addition, both ACC and HDAC6 inhibitions block key platelet cytoskeleton signaling events, including Rac1 GTPase activation and the phosphorylation of its downstream effector, p21-activated kinase 2 (PAK2). However, neither CP640.186 nor tubacin affects thrombin-induced actin cytoskeleton remodeling, while ACC inhibition results in decreased thrombin-induced reactive oxygen species (ROS) production and extracellular signal-regulated kinase (ERK) phosphorylation. We conclude that when using washed human platelets, ACC inhibition limits tubulin deacetylation upon thrombin stimulation, which in turn impairs platelet aggregation. The mechanism involves a downregulation of the Rac1/PAK2 pathway, being independent of actin cytoskeleton.

Keywords: Rac1 signaling; acetyl-CoA carboxylase; acetylation; actin cytoskeleton; platelet; platelet aggregation; tubulin

DOI: https://doi.org/10.3390/ijms222313129