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

• Published in: Cell death & disease Vol. 15; no. 10; pp. 758 - 17
• Main Authors: Feng, Maoxiao, Jiao, Qinlian, Ren, Yidan, Liu, Xiaoyan, Gao, Zihan, Li, Zhengjun, Wang, Yunshan, Zhao, Miaoqing, Bi, Lei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.10.2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 38; 38/91; 631/67/1059; 692/308/409; Adenocarcinoma; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Carcinogenesis; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Biology; Cell Culture; Cell Line, Tumor; Chromatin; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Gastrointestinal tract; Gemcitabine; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Glycolysis; Glycolysis - drug effects; Humans; Immunology; Life Sciences; Metastases; Mice; Microenvironments; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Patients; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; Tumor Microenvironment - drug effects; Tumors; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-07145-z

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.