PRMT5 enhances tumorigenicity and glycolysis in pancreatic cancer via the FBW7/cMyc axis

Abstract

Background 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. 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. Methods Real-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 18 F-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. Results PRMT5 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. Conclusions The 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. Electronic supplementary material The online version of this article (10.1186/s12964-019-0344-4) contains supplementary material, which is available to authorized users.

Protein arginine methyltransferase 5 promotes cholesterol biosynthesis–mediated Th17 responses and autoimmunity

“…PRMT5 plays crucial roles in carcinogenesis (39,40) and autoimmune pathogenesis (8). Although multiple mechanisms tightly control PRMT5 expression in nontransformed T cells (9), uncontrolled PRMT5 expression is a hallmark of hematologic and solid oncogenic tumors (41)(42)(43)(44)(45). The driver role of PRMT5 in cancer has led to efforts to develop PRMT5-selective inhibitors as a therapy for solid and hematologic cancers that are currently being tested for safety and efficacy (Clinicaltrials.gov, registration ID: NCT03573310, NCT03854227, NCT02783300, NCT03614728).…”

<p>PRMT5 Promotes Aerobic Glycolysis and Invasion of Breast Cancer Cells by Regulating the LXRα/NF-κBp65 Pathway</p>

“…In the procession of tumors, due to the nutritional supply disorder caused by abnormal oxygen and blood vessels, tumor cells have to undergo metabolic reprogramming to maintain their proliferation, and the main characterization of metabolic reprogramming is aerobic glycolysis. 9 A previous study revealed that PRMT5 could intensify the glycolysis of pancreatic cancer, 10 but there was no study on the effect of PRMT5 on the metabolism of BC and its mechanism. Liver X receptor α (LXRα), as a member of the nuclear receptor family, plays an important role in glucose metabolism and inflammatory response, 11 and in recent years, a study has found its important role in the development and progression of tumors.…”

PRMT5 promotes epithelial‐mesenchymal transition via EGFR‐β‐catenin axis in pancreatic cancer cells

“…21 More recently, PRMT5 was demonstrated that lead to FBW7 expression to promote tumorigenesis in pancreatic cancer. 14 ling, 24 and EGF-induced nuclear translocation of SHCBP1 directly increased acetylation of β-catenin to enhanced NSCLC cellular stemness, 25 which is suggested that EGFR signalling can drive β-catenin activation via various routes. In this study, we provide a novel F I G U R E 2 PRMT5 promotes cell proliferation in pancreatic cancer cells and tumorigenesis.…”

“…13 In addition, PRMT5 was proved to inhibit the tumour suppressor FBW7, resulting in increasing c-Myc levels to promote the proliferation of and aerobic glycolysis in pancreatic cancer cells. 14 In this study, we examined the roles of PRMT5 in pancreatic cancer and elucidated the underlying mechanism. Our data showed that PRMT5 promoted cell proliferation, migration and invasion in pancreatic cancer cells, and promoted tumorigenesis.…”