Abstract
BackgroundThe epigenetic factor protein arginine methyltransferase 5 (PRMT5) has been reported to play vital roles in a wide range of cellular processes, such as gene transcription, genomic organization, differentiation and cell cycle control. However, its role in pancreatic cancer remains unclear. Our study aimed to investigate the roles of PRMT5 in pancreatic cancer prognosis and progression and to explore the underlying molecular mechanism.MethodsReal-time PCR, immunohistochemistry and analysis of a dataset from The Cancer Genome Atlas (TCGA) were performed to study the expression of PRMT5 at the mRNA and protein levels in pancreatic cancer. Cell proliferation assays, including cell viability, colony formation ability and subcutaneous mouse model assays, were utilized to confirm the role of PRMT5 in cell proliferation and tumorigenesis. A Seahorse extracellular flux analyzer, a glucose uptake kit, a lactate level measurement kit and the measurement of 18F-FDG (fluorodeoxyglucose) uptake by PET/CT (positron emission tomography/computed tomography) imaging were used to verify the role of PRMT5 in aerobic glycolysis, which sustains cell proliferation. The regulatory effect of PRMT5 on cMyc, a master regulator of oncogenesis and aerobic glycolysis, was explored by quantitative PCR and protein stability measurements.ResultsPRMT5 expression was significantly upregulated in pancreatic cancer tissues compared with that in adjacent normal tissues. Clinically, elevated expression of PRMT5 was positively correlated with worse overall survival in pancreatic cancer patients. Silencing PRMT5 expression inhibited the proliferation of pancreatic cancer cells both in vitro and in vivo. Moreover, PRMT5 regulated aerobic glycolysis in vitro in cell lines, in vivo in pancreatic cancer patients and in a xenograft mouse model used to measure 18F-FDG uptake. We found that mechanistically, PRMT5 posttranslationally regulated cMyc stability via F-box/WD repeat-containing protein 7 (FBW7), an E3 ubiquitin ligase that controls cMyc degradation. Moreover, PRMT5 epigenetically regulated the expression of FBW7 in pancreatic cancer cells.ConclusionsThe present study demonstrated that PRMT5 epigenetically silenced the expression of the tumor suppressor FBW7, leading to increased cMyc levels and the subsequent enhancement of the proliferation of and aerobic glycolysis in pancreatic cancer cells. The PRMT5/FBW7/cMyc axis could be a potential therapeutic target for the treatment of pancreatic cancer.
Highlights
The epigenetic factor protein arginine methyltransferase 5 (PRMT5) has been reported to play vital roles in a wide range of cellular processes, such as gene transcription, genomic organization, differentiation and cell cycle control
In hepatocellular carcinoma (HCC), upregulation of PRMT5 correlated with a worse prognosis, and PRMT5 could regulate the proliferation of HCC cells in vitro [14]
Analysis of tumor glucose uptake in pancreatic cancer patients To assess the correlation between PRMT5 and glucose uptake in pancreatic cancer patients, we examined the SUVmax in pancreatic cancer patients via Positron emission tomography and computed tomography (PET/CT) imaging, a technique that measures glucose uptake via glycolysis by assessing 18F-FDG uptake
Summary
The epigenetic factor protein arginine methyltransferase 5 (PRMT5) has been reported to play vital roles in a wide range of cellular processes, such as gene transcription, genomic organization, differentiation and cell cycle control. Our study aimed to investigate the roles of PRMT5 in pancreatic cancer prognosis and progression and to explore the underlying molecular mechanism. Significant progress has been made in past decades in the diagnosis and treatment of pancreatic cancer, the overall 5-year survival rate of patients remains steady, at approximately 6% [1, 2]. The expression of PRMT5 has been reported to be correlated with poor prognosis in patients with different cancer types [12]. The importance of the major downstream target of CDKN2A deletion, PRMT5, in pancreatic cancer has seldom been discussed. It is of vital importance to uncover the roles of PRMT5 in pancreatic cancer with an aim to identify novel prognostic and treatment targets
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