Targeting protein arginine methyltransferase 5 inhibits colorectal cancer growth by decreasing arginine methylation of eIF4E and FGFR3

Abstract

Protein arginine methyltransferases (PRMTs) plays critical roles in cancer. PRMT5 has been implicated in several types of tumors. However, the role of PRMT5 in cancer development remains to be fully elucidated. Here, we provide evidence that PRMT5 is overexpressed in colorectal cancer (CRC) cells and patient-derived primary tumors, correlated with increased cell growth and decreased overall patient survival. Arginine methyltransferase inhibitor 1 (AMI-1)strongly inhibited tumor growth, increased the ratio of Bax/Bcl-2, and induced apoptosis in mouse CRC xenograt model. AMI-1 also induced apoptosis and decreased the migratory activity in several CRC cells. In CRC xenografts AMI-1 significantly decreased symmetric dimethylation of histone 4 (H4R3me2s), a histone mark of type II PRMT5, but not the expression of H4R3me2a, a histone mark of type I PRMTs. These results suggest that the inhibition of PRMT5 contributes to the antitumor efficacy of AMI-1. Chromatin immunoprecipitation (ChIP) identified FGFR3 and eIF4E as two key genes regulated by PRMT5. PRMT5 knockdown reduced the levels of H4R3me2s and H3R8me2s methylation on FGFR3 and eIF4E promoters, leading to decreased expressions of FGFR3 and eIF4E. Collectively, our findings provide new evidence that PRMT5 plays an important role in CRC pathogenesis through epigenetically regulating arginine methylation of oncogenes such as eIF4E and FGFR3.

Anguilla japonica lectin 1 delivery through adenovirus vector induces apoptotic cancer cell death through interaction with PRMT5

“…Through cooperation with cyclin D1, PRMT5 inhibits p53‐dependent tumor suppression, thereby facilitating lymphomagenesis . In addition, PRMT5 has been extensively studied as a therapeutic target in various cancers, including colorectal cancer , neuroblastoma and B‐cell lymphoma . Transcription factor E2F‐1 has been determined to be a direct substrate for PRMT1 and PRMT5, and E2F‐1 methylated by PRMT1 prevents its methylation by PRMT5 and induces E2F‐1‐dependent cell apoptosis, whereas E2F‐1 methylated by PRMT5 antagonizes its methylation by PRMT1 and favors cell proliferation , suggesting a key role of differed arginine methylation in determining E2F‐1 biological activities.…”

“…Through cooperation with cyclin D1, PRMT5 inhibits p53-dependent tumor suppression, thereby facilitating lymphomagenesis [53]. In addition, PRMT5 has been extensively studied as a therapeutic target in various cancers, including colorectal cancer [54], neuroblastoma [55] and B-cell lymphoma [56].…”

SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth

“…PRMT5 catalyzes the monomethylation and symmetric dimethylation of arginine (SDME-RG) in diverse substrates such as histones and nonhistone proteins involved in transcription, splicing, and translation as well as other cellular processes. PRMT5 was previously shown to affect TP53, the eukaryotic translation initiation factor eIF4E, the androgen receptor, and the epidermal growth factor receptor, pointing to a potentially important role in cancer biology (10)(11)(12). PRMT5 is inhibited by 5′-O-methylthioadenosine (MTA), the substrate of methylthioadenosine phosphorylase (MTAP), which is a key enzyme in the methionine salvage pathway.…”

PRMT5 is essential for the maintenance of chondrogenic progenitor cells in the limb bud

“…Regulating a diverse set of target proteins, it can methylate specific Sm proteins, facilitating their assembly into a core complex of spliceosomal snRNPs (Chari et al, 2008;Meister and Fischer, 2002;Neuenkirchen et al, 2015;Pelz et al, 2015). Additionally, PRMT5 can regulate gene expression by methylation of histones H2A/H4 and H3 (specifically H2A/H4R3 and H3R8), which are generally associated with transcriptional repression (Ancelin et al, 2006;Di Lorenzo and Bedford, 2011;Lee and Bedford, 2002;Tee et al, 2010;Zhang et al, 2015;Zhao et al, 2009).…”