The interaction between UBR7 and PRMT5 drives PDAC resistance to gemcitabine by regulating glycolysis and immune microenvironment.

Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101524092 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-4889 (Electronic) NLM ISO Abbreviation: Cell Death Dis Subsets: MEDLINE

Original Publication: London : Nature Pub. Group

Carcinoma, Pancreatic Ductal*/drug therapy ; Carcinoma, Pancreatic Ductal*/genetics ; Carcinoma, Pancreatic Ductal*/pathology ; Carcinoma, Pancreatic Ductal*/metabolism ; Deoxycytidine*/analogs & derivatives ; Deoxycytidine*/pharmacology ; Deoxycytidine*/therapeutic use ; Drug Resistance, Neoplasm*/genetics ; Drug Resistance, Neoplasm*/drug effects ; Gemcitabine* ; Glycolysis*/drug effects ; Pancreatic Neoplasms*/drug therapy ; Pancreatic Neoplasms*/genetics ; Pancreatic Neoplasms*/pathology ; Pancreatic Neoplasms*/metabolism ; Protein-Arginine N-Methyltransferases*/metabolism ; Protein-Arginine N-Methyltransferases*/genetics ; Tumor Microenvironment*/drug effects; Animals ; Humans ; Mice ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic/drug effects ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitin-Protein Ligases/genetics

Pancreatic ductal adenocarcinoma (PDAC) is a common malignant tumor of the digestive tract. Although gemcitabine and other therapeutic agents are effective in patients with advanced and metastatic pancreatic cancer, drug resistance has severely limited their use. However, the mechanisms of gemcitabine resistance in pancreatic cancer are poorly understood. In this study, ATAC-seq, ChIP-seq, and RNA-seq were performed to compare chromatin accessibility and gene expression in a patient-derived tumor xenograft (PDX) model of pancreatic cancer with or without gemcitabine resistance. Analyzing these sequencing data, we found a dramatic change in chromatin accessibility in the PDX model of gemcitabine-resistant tissues and identified a key gene, UBR7, which plays an important role in mediating gemcitabine resistance. Further research found that depletion of UBR7 significantly increased pancreatic carcinogenesis and the immunosuppressive microenvironment. Mechanistically, depleted UBR7 increased the stability of PRMT5, thereby promoting glycolysis in pancreatic cancer cells. Finally, an inhibitor that blocks PRMT5 (DS-437) significantly reduced gemcitabine resistance in pancreatic cancer caused by UBR7 depletion. In conclusion, our results illustrate that the UBR7-PRMT5 axis is a key metabolic regulator of PDAC and a promising target for the clinical treatment of gemcitabine resistance in PDAC.
(© 2024. The Author(s).)

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82372616 National Natural Science Foundation of China (National Science Foundation of China); 82172350 National Natural Science Foundation of China (National Science Foundation of China); 82303153 National Natural Science Foundation of China (National Science Foundation of China); 82071035 National Natural Science Foundation of China (National Science Foundation of China); 82371165 National Natural Science Foundation of China (National Science Foundation of China); ZR2022LZL001 Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)

0W860991D6 (Deoxycytidine)
0 (Gemcitabine)
EC 2.1.1.319 (PRMT5 protein, human)
EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)
0 (UBR7 protein, human)

Date Created: 20241018 Date Completed: 20241018 Latest Revision: 20241022

20241022

PMC11489413

10.1038/s41419-024-07145-z

39424627