O-GlcNAcylation of ZEB1 facilitated mesenchymal pancreatic cancer cell ferroptosis

Abstract

Background: Mesenchymal cancer cells, resistant to the traditional regulated cell death, are exquisitely vulnerable to ferroptosis. However, the underlying mechanism has been rarely studied. While glycolipid metabolism rewiring is a critical determination of both cancer cell mesenchymal phenotype and cell death resistance, we are interested in the underlying cross talk between glycolipid metabolism and mesenchymal cancer cell ferroptosis sensitivity. Methods: CCK-8, western blot and clone forming assay were used to access the effect of glucose on mesenchymal cancer cell ferroptosis susceptibility and O-GlcNAcylation level. GEPIA database, shRNA knockdown and various pharmacological inhibitors were used to analyze the relationship between O-GlcNAcylation and mesenchymal cancer cell ferroptosis in vitro and in vivo. A series of experiments were conducted to investigate the underlying mechanisms of glucose induced ZEB1 O-GlcNAcylation on mesenchymal cancer cell ferroptosis susceptibility. Results: Mesenchymal pancreatic cancer cells O-GlcNAcylation level and ferroptosis cell death was significantly increased under high glucose condition in vitro and in vivo. O-GlcNAcylation of ZEB1, rather than other transcription factors, was involved in this process. Mechanistically, glucose triggered ZEB1 O-GlcNAcylation at Ser555 site enhanced its stabilization and nuclear translocation, induced lipogenesis associated genes, FASN and FADS2, transcription activity, which ultimately resulted in lipid peroxidation dependent mesenchymal pancreatic cancer cell ferroptosis. Conclusions: These results identify a novel role of glycolipid metabolism and O-GlcNAcylation in mesenchymal cancer cells ferroptosis susceptibility, which broaden the molecular mechanism of ferroptosis and suggested a potential clinical therapeutic strategy for refractory tumors.

Targeting USP8 Inhibits O‐GlcNAcylation of SLC7A11 to Promote Ferroptosis of Hepatocellular Carcinoma via Stabilization of OGT

“…[ 69 ] O‐GlcNAcylation of ZEB1 also promotes the transcriptional activity of adipogenesis‐related genes FASN and FADS2, leading to increased synthesis of PUFAs and activating ferroptosis. [ 63 ] O‐GlcNAcylation of the ferritin heavy chain at S179 inhibits its interaction with NCOA4, the ferritinophagy receptor, thereby preventing cells from ferroptosis. [ 29 ] In the present study, we found that ectopic expression of SLC7A11‐S26A mutant could not recover the cystine uptake in SLC7A11‐KO cells.…”

“…The O‐GlcNAcylation of ZEB1 at Ser555 site enhances its stabilization and nuclear translocation and induces lipogenesis‐associated gene transcription activity, which ultimately results in lipid peroxidation‐dependent mesenchymal pancreatic cancer cell ferroptosis. [ 63 ] However, the O‐GlcNAcylation of SLC7A11 has not been investigated yet. Our present study reveals a previously unrecognized post‐translational modification of SLC7A11 in HCC, which was mainly regulated by USP8‐OGT axis.…”

“…Increased total O-GlcNAcylation is a general characteristic of cancer cells, that regulates multiple cancer cell phenotypes. [63][64][65][66] O-GlcNAcylation has been reported to play multiple roles in ferroptosis. [67] O-GlcNAcylation of c-Jun stimulates GSH synthesis and reduces ROS accumulation, thus inhibiting ferroptosis.…”

Control of lipid metabolism by the dynamic and nutrient‐dependent post‐translational modification O‐GlcNAcylation

“…Recently, it has been found in mesenchymal pancreatic cancer cells that FASN and fatty acid desaturase‐2 (FADS2) expression are connected to the O ‐GlcNAcylation status of the transcription factor zinc finger E‐box‐binding homeobox‐1 (ZEB‐1) at Ser555 67 . The authors highlighted a mechanism by which glucose contributes to mesenchymal pancreatic cancer cells ferroptosis through an O ‐GlcNAcylation‐FASN‐FADS2 axis.…”

GAPDH Is a Novel Ferroptosis-Related Marker and Correlates with Immune Microenvironment in Lung Adenocarcinoma

“…Ferroptosis is controlled by a variety of cellular metabolic pathways, including amino acid metabolism, redox homeostasis, and mitochondrial activity [ 9 ]. In parallel to the metabolism of lipids and amino acids, the effect of glucose, a key fuel source for energy metabolism, also needs to be investigated in the ferroptosis process of cancer cells [ 10 ].…”