PRMT5 Is a Critical Regulator of Breast Cancer Stem Cell Function via Histone Methylation and FOXP1 Expression

Chiang, Kelly; Zielińska, Agnieszka; Shaaban, Abeer M.; Sánchez-Bailón, María Pilar; Jarrold, James; Clarke, Thomas L.; Zhang, Jingxian; Francis, Adele; Jones, Louise; Smith, Sally; Barbash, Olena; Guccione, Ernesto; Farnie, Gillian; Smalley, Matthew J.; Davies, Clare C.

doi:10.1016/j.celrep.2017.11.096

Cited by 155 publications

(138 citation statements)

References 47 publications

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“…The PRMT5 gene encodes an arginine methyltransferase, which catalyzes the transfer of methyl groups to the amino acid arginine in target proteins, including histones, and promotes target gene transcription. A wealth of literature supports the view that PRMT5 plays a vital role in regulating cancer progression via histone methylation 49 - 51 . PRMT5 promotes the cancer stem cell function of breast cancer by enhancing the enrichment of H3K4me3 on the FOXP1 promoter and subsequently driving FOXP1 transcription and expression 49 .…”

Section: Discussionmentioning

confidence: 89%

“…A wealth of literature supports the view that PRMT5 plays a vital role in regulating cancer progression via histone methylation 49 - 51 . PRMT5 promotes the cancer stem cell function of breast cancer by enhancing the enrichment of H3K4me3 on the FOXP1 promoter and subsequently driving FOXP1 transcription and expression 49 . SHARPIN augments invasiveness of lung cancer by interacting with PRMT5, which methylates histones H3 and H4, subsequently upregulating metastasis-related gene expression 50 .…”

Section: Discussionmentioning

confidence: 89%

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Overexpression of HOXC10 promotes angiogenesis in human glioma via interaction with PRMT5 and upregulation of VEGFA expression

Tan

Chen

et al. 2018

Theranostics

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High levels of angiogenesis are associated with poor prognosis in patients with gliomas. However, the molecular mechanisms underlying tumor angiogenesis remain unclear.Methods: The effect of homeobox C10 (HOXC10) on tube formation, migration, and proliferation of human umbilical vein endothelial cells (HUVECs) and on chicken chorioallantoic membranes (CAMs) was examined. An animal xenograft model was used to examine the effect of HOXC10 on xenograft angiogenesis or the effect of bevacizumab, a monoclonal antibody against vascular endothelial growth factor A (VEGFA), on HOXC10-overexpressing xenografts. A chromatin immunoprecipitation assay was applied to investigate the mechanism in which HOXC10 regulated VEGFA expression.Results: Overexpressing HOXC10 enhanced the capacity of glioma cells to induce tube formation, migration and proliferation of HUVECs, and neovascularization in CAMs, while silencing HOXC10 had the opposite result. We observed that CD31 staining was significantly increased in tumors formed by HOXC10-overexpressing U251MG cells but reduced in HOXC10-silenced tumors. Mechanistically, HOXC10 could transcriptionally upregulate VEGFA expression by binding to its promoter. Strikingly, treatment with bevacizumab, a monoclonal antibody against VEGFA, significantly inhibited the growth of HOXC10-overexpressing tumors and efficiently impaired angiogenesis. Protein arginine methyltransferase 5 (PRMT5) and WD repeat domain 5 (WDR5), both of which regulate histone post-translational modifications, were required for HOXC10-mediated VEGFA upregulation. Importantly, a significant correlation between HOXC10 levels and VEGFA expression was observed in a cohort of human gliomas.Conclusions: This study suggests that HOXC10 induces glioma angiogenesis by transcriptionally upregulating VEGFA expression, and may represent a potential target for antiangiogenic therapy in gliomas.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 89%

Overexpression of HOXC10 promotes angiogenesis in human glioma via interaction with PRMT5 and upregulation of VEGFA expression

Tan

Chen

et al. 2018

Theranostics

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“…Conversely, phosphorylation of MEP50 on Thr5 increases the methyltransferase activity of PRMT5‐MEP50 toward histone H4 . In BCSCs, PRMT5 was reported to interact with FOXP1, and authors speculated that the interaction could be targeted using small inhibitor molecules . This was recently applied in mantle cell lymphoma, in which a selective PRMT5 inhibitor was generated offering a promising therapeutic strategy …”

Section: Introductionmentioning

confidence: 99%

“…25 In BCSCs, PRMT5 was reported to interact with FOXP1, and authors speculated that the interaction could be targeted using small inhibitor molecules. 18 This was recently applied in mantle cell lymphoma, in which a selective PRMT5 inhibitor was generated offering a promising therapeutic strategy. 26 Here, based on the analysis of a large cohort of patients with breast tumors, we identified a new PRMT5 interactor, the liver kinase B1 protein (LKB1), a master kinase that acts as a key regulator of cell polarity, energy metabolism and mTOR signaling.…”

Section: Introductionmentioning

confidence: 99%

LKB1 regulates PRMT5 activity in breast cancer

Lattouf

Kassem

Jacquemetton

et al. 2018

Intl Journal of Cancer

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Protein arginine methyltransferase 5 (PRMT5) is the main enzyme responsible for the symmetrical dimethylation of arginine residues on target proteins in both the cytoplasm and the nucleus. Though its activity has been associated with tumor progression in various cancers, the expression pattern of this oncoprotein has been scarcely studied in breast cancer. In the current work, we analyzed its expression in a large cohort of breast cancer patients, revealing higher nuclear PRMT5 levels in ERα‐positive tumors and an association with prolonged disease free and overall survival. Interestingly, high PRMT5 nuclear expression was also associated with higher nuclear liver kinase B1 (LKB1), suggesting that a functional relationship may occur. Consistently, several approaches provided evidence that PRMT5 and LKB1 interact directly in the cytoplasm of mammary epithelial cells. Moreover, although PRMT5 is not able to methylate LKB1, we found that PRMT5 is a bona fade substrate for LKB1. We identified T132, 139 and 144 residues, located in the TIM‐Barrel domain of PRMT5, as target sites for LKB1 phosphorylation. The point mutation of PRMT5 T139/144 to A139/144 drastically decreased its methyltransferase activity, due probably to the loss of its interaction with regulatory proteins such as MEP50, pICln and RiOK1. In addition, modulation of LKB1 expression modified PRMT5 activity, highlighting a new regulatory mechanism that could have clinical implications.

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“…The PRMT5-WDR 77 activity is necessary for TGF-β dependent EMT and metastatic processes that are associated with (i) PRMT-dependent R2 methylation and (ii) regulation of critical genes linked with TGF-beta-dependent cancer cell invasion pathways (Chen et al 2017). Chiang et al (2017) reported PRMT5 recruitment to the FOXP1 promoter drives breast cancer stem cell (BCSC) proliferation facilitated by H3R2 dimethylation and H3K4 trimethylation (Chiang et al 2017). They further discussed the implications of inhibiting PRMT5 on BCSC stem cells and potential for decreasing rates of tumour relapse (Chiang & Davies 2018).…”

Section: Protein Arginine Methyltransferasementioning

confidence: 99%

Epigenetic arginine methylation in breast cancer: emerging therapeutic strategies

Wang

Dowhan

Muscat

2019

Journal of Molecular Endocrinology

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Breast cancer is a heterogeneous disease, and the complexity of breast carcinogenesis is associated with epigenetic modification. There are several major classes of epigenetic enzymes that regulate chromatin activity. This review will focus on the nine mammalian protein arginine methyltransferases (PRMTs) and the dysregulation of PRMT expression and function in breast cancer. This class of enzymes catalyse the mono- and (symmetric and asymmetric) di-methylation of arginine residues on histone and non-histone target proteins. PRMT signalling (and R methylation) drives cellular proliferation, cell invasion and metastasis, targeting (i) nuclear hormone receptor signalling, (ii) tumour suppressors, (iii) TGF-β and EMT signalling and (iv) alternative splicing and DNA/chromatin stability, influencing the clinical and survival outcomes in breast cancer. Emerging reports suggest that PRMTs are also implicated in the development of drug/endocrine resistance providing another prospective avenue for the treatment of hormone resistance and associated metastasis. The complexity of PRMT signalling is further underscored by the degree of alternative splicing and the scope of variant isoforms (with distinct properties) within each PRMT family member. The evolution of PRMT inhibitors, and the ongoing clinical trials of PRMT inhibitors against a subgroup of solid cancers, coupled to the track record of lysine methyltransferases inhibitors in phase I/II clinical trials against cancer underscores the potential therapeutic utility of targeting PRMT epigenetic enzymes to improve survival outcomes in aggressive and metastatic breast cancer.

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PRMT5 Is a Critical Regulator of Breast Cancer Stem Cell Function via Histone Methylation and FOXP1 Expression

Cited by 155 publications

References 47 publications

Overexpression of HOXC10 promotes angiogenesis in human glioma via interaction with PRMT5 and upregulation of VEGFA expression

Overexpression of HOXC10 promotes angiogenesis in human glioma via interaction with PRMT5 and upregulation of VEGFA expression

LKB1 regulates PRMT5 activity in breast cancer

Epigenetic arginine methylation in breast cancer: emerging therapeutic strategies

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