Role of PRMT1 and PRMT5 in Breast Cancer

Abstract

Breast cancer is the most common cancer diagnosed in women worldwide. Early-stage breast cancer is curable in ~70-80% of patients, while advanced metastatic breast cancer is considered incurable with current therapies. Breast cancer is a highly heterogeneous disease categorized into three main subtypes based on key markers orientating specific treatment strategies for each subtype. The complexity of breast carcinogenesis is often associated with epigenetic modification regulating different signaling pathways, involved in breast tumor initiation and progression, particularly by the methylation of arginine residues. Protein arginine methyltransferases (PRMT1-9) have emerged, through their ability to methylate histones and non-histone substrates, as essential regulators of cancers. Here, we present an updated overview of the mechanisms by which PRMT1 and PRMT5, two major members of the PRMT family, control important signaling pathways impacting breast tumorigenesis, highlighting them as putative therapeutic targets.

Keywords: PRMT1; PRMT5; arginine methylation; breast cancer; cell signaling; transcriptional regulation.

Figure 1

Association of PRMT1 expression and relapse-free survival (RFS) in breast cancer subtypes. Kaplan–Meier curves created by the public database and web application KM plotter. Molecular subtypes are based on St Gallen criteria [33].

Figure 2

PRMT1 in breast cancer. (A). Upon IGF-1 stimulation, PRMT1 methylates Erα. IGF-1R phosphorylates IRS1 and SHC on tyrosine residues leading to the recruitment of PI3K and GRB2, activating AKT and ERK pathways. (B). PRMT1 controls the cellular localization of BRCA1 and facilitates DNA homologous recombination and upregulates the anti-apoptotic protein BCL2. (C). Without progesterone, PRMT1 interacts with PR and forms a repressor complex with other corepressors to regulate the expression of a subtype of target genes. After progesterone stimulation, chromatin opening allows the recruitment of PR coactivators, including PRMT1 which methylates PR on arginine 637 to regulate the expression of progesterone responsive genes. (D). PRMT1 methylates ERα at R260 residue in response to estrogen, resulting in the formation of a complex containing mERα, the p85 subunit of PI3K, SRC, and the focal adhesion kinase (FAK), and activating MAPK and AKT signaling cascades. (E). PRMT1-dependent methylation of C/EBPα promotes expression of cyclin D1 by blocking the interaction between C/EBPα and its corepressor HDAC3. (F). Methylation of EZH2 by PRMT1 regulates its stability and promotes EMT and breast cancer metastasis. (G). PRMT1 is recruited to the promoter region of EGFR, LRP5, PORCN, and ZEB1 and catalyzes H4R3 methylation to promote genes expression.

Figure 3

Association of PRMT5 expression and relapse-free survival (RFS) in breast cancer subtypes. Kaplan–Meier curves created by the public database and web application KM plotter. Molecular substypes are based on St Gallen criteria [33].

Figure 4

PRMT5 in breast cancer (A). PRMT5 promotes aerobic glycolysis and invasion of BC cells by regulating the LXRα/NF-κBp65 pathway. (B). PRMT5 interacts with KLF4 and KLF5 and regulates their methylation and stability. Stabilization of KLF4 and KLF5 in BC cells increases the expression of oncogenic pathways such as EGF/EGFR, MAPK, and CDK1 and cell proliferation, BCSC maintenance, and metastasis. (C). PRMT5 activates Wnt/β-catenin signaling via epigenetic silencing of DKK1 and DKK3. (D). SNAI2 interacts with PRMT5 and KDM1A and is recruited to the E-cadherin promoter region. PRMT5 catalyzes H4R3me2s, and KDM1A mediates the demethylation of H3K4me2, inhibiting E-cadherin expression. PRMT5 catalyzes H3R2me2s, and KDM1A removes H3K9me2 on the vimentin promoter to function as a transcriptional coactivator. (E). PRMT5 recruitment to the FOXP1 promoter facilitates H3R2me2s, SET1 recruitment, H3K4me3, and FOXP1 gene expression.

Figure 5

Dual role of PRMT5 in breast cancer. In TNBC, upon GC treatment, PRMT5 triggers the interaction between GR and HP1γ regulating cell migration independently of its enzymatic activity. In luminal BC, tamoxifen induces PRMT5 translocation and ERα methylation to recruit corepressor complexes that inhibit transcription.