Wenyan Xu, Yi Qin, Bo Zhang, Si Shi, Shunrong Li, Jiang Liu, Jiang Long, Chen Liu, Liang Liu, Jin Xu, Xianjun Yu

Department of Pancreatic Oncology, Fudan University Shanghai Cancer Center

Objective:Pancreatic cancer is one of the most intractable and fatal cancer and biologically characterized by high degrees of hypoxia. Here, we describe PRMT5 (protein arginine methltransferase 5), a histone arginine methyltransferase that senses and mediates rRNA transcription under hypoxic status, thus protects cells from hypoxia-dependent apoptosis. Method:we treated pancreatic cancer cells PANC-1 and MIA PaCa-2 with CoCl2 (150 μm, 8H), a chemical reagent that induced expression of HIF1α, and mimics hypoxia stress. ChIP assay with PRMT5 antibody was performed to observe the change in occupancy of PRMT5 in rDNA chromatin upon CoCl2treatment. We generated PRMT5 knock-down PANC-1 and MIA PaCa-2 cell lines (Figure 3A), and treated these cell lines with CoCl2 to find out whether PRMT5 protects pancreatic cancer cells from apoptosis under hypoxia conditions through reduction in rRNA transcription and ribosome synthesis. Finally, the immunohistochemical assay was performed to show the distribution of PRMT5 in pancreatic cancer patient samples. Result: Our results from this study indicated that hypoxia triggered down-regulation of rRNA transcription and up-regulation of PRMT5 protein level, which suggest potential role of PRMT5 in hypoxia stress adaptation through decreased rRNA synthesis. Our results also suggest that PRMT5 protected pancreatic cancer cells from hypoxia induced apoptosis, which prompted us to speculate that intervention of PRMT5 could lead to apoptosis of the hypoxic cancer cells, which were originally resistant to chemotherapy. Conclusion: Our present study shed light on pancreatic cancer adaptations to hypoxia from a quite novel aspect through down-regulation of rRNA synthesis, which limit energy use under hypoxia conditions. PRMT5, as an important epigenetic chromatin modifier, senses the energy status and repressed rRNA synthesis. Further studies are ongoing to determine the roles of PRMT5 in pancreatic cancer, elucidate the detailed mechanism of PRMT5 in energy sensing and rRNA transcriptional regulation.

Key Words: Pancreatic cancer  PRMT5  cancer metabolism