DHHC9-mediated GLUT1 S-palmitoylation promotes glioblastoma glycolysis and tumorigenesis

Abstract

Glucose transporter GLUT1 is a transmembrane protein responsible for the uptake of glucose into the cells of many tissues through facilitative diffusion. Plasma membrane (PM) localization is essential for glucose uptake by GLUT1. However, the mechanism underlying GLUT1 PM localization remains enigmatic. We find that GLUT1 is palmitoylated at Cys207, and S-palmitoylation is required for maintaining GLUT1 PM localization. Furthermore, we identify DHHC9 as the palmitoyl transferase responsible for this critical posttranslational modification. Knockout of DHHC9 or mutation of GLUT1 Cys207 to serine abrogates palmitoylation and PM distribution of GLUT1, and impairs glycolysis, cell proliferation, and glioblastoma (GBM) tumorigenesis. In addition, DHHC9 expression positively correlates with GLUT1 PM localization in GBM specimens and indicates a poor prognosis in GBM patients. These findings underscore that DHHC9-mediated GLUT1 S-palmitoylation is critical for glucose supply during GBM tumorigenesis.

Achieving CD8+ T cell-dependent lethality by targeting cancer USP14 in hepatocellular carcinoma

“…GLUT1, as an important transmembrane protein, regulates the entry of extracellular glucose into cells and serves as a "valve" to control the constant glucose uptake by cells [33]. In previous studies, GLUT1 was reported to be increasingly expressed in many malignant tumors and correlated with poor clinical outcomes, thus GLUT1 was considered a main prognostic indicator for tumorigenesis [34][35][36]. Few studies have explored the role of GLUT1 in immunoregulation in HCC.…”

Emerging roles of protein palmitoylation and its modifying enzymes in cancer cell signal transduction and cancer therapy

“…In addition, palmitoylation at the C-terminal of GSDME, a member of the cleavage of gasdermin family proteins, can enhance chemotherapeutic drug-induced pyroptosis by modulating GSDME-mediated downstream signal 95 . ZDHHC9 facilitates palmitoylation of Glucose transporter (GLUT1) at Cys207 and thus increases its plasma membrane localization, which is critical for glucose supply during glioblastoma (GBM) tumorigenesis 96 . Palmitoylation of Smad3 catalyzed by ZDHCH19 promotes the activation of the Transforming Growth Factor-beta (TGF-β) signaling pathway and its interaction with EP300, and enhances expression of mesenchymal markers in the mesenchymal subtype of GBM 97 .…”

Metabolic Adaptation-Mediated Cancer Survival and Progression in Oxidative Stress

“…The wide application of 2-flourine-18[(18)F] fluoro-2-deoxy-D-glucose (FDG) positron emission tomography–computed tomography (PET–CT) demonstrated the glycolytic phenotype in most cancers. Therefore, ROS-induced oxidation and inactivation of GAPDH and PKM2 can cause the depression of both aerobic and anaerobic glycolysis, leading to decreased proliferation and/or cell death due to shortages of energy and tricarboxylic acid cycle (TCA)-derived biosynthesis, especially in cancer cells in early stages that are more dependent on glycolysis [ 10 , 11 , 12 ]. Despite these reports linking overt ROS damage to metabolic pathways and other cellular components, it is noteworthy that cancer cells also adapt to such overwhelming ROS levels and metabolic impairment [ 13 , 14 ].…”