Genetic Validation of the Protein Arginine Methyltransferase PRMT5 as a Candidate Therapeutic Target in Glioblastoma

Yan, Fengjun; Alinari, Lapo; Lustberg, Mark; Martin, Ludmila Katherine; Cordero-Nieves, Hector M.; Banasavadi-Siddegowda, Yeshavanth; Virk, Selene; Barnholtz‐Sloan, Jill S.; Bell, Erica H.; Wojton, Jeffrey; Jacob, Naduparambil K.; Chakravarti, Arnab; Nowicki, Michal O.; Wu, Xin; Lapalombella, Rosa; Datta, Jharna; Yu, Bo; Gordon, Kate; Haseley, Amy; Patton, John T.; Smith, Porsha L.; Ryu, John; Zhang, Xiaoli; Mo, Xiaokui; Marcucci, Guido; Nuovo, Gerard J.; Kwon, Chil Hun; Byrd, John C.; Chiocca, E. Antonio; Li, Chenglong; Sif, Saı̈d; Jacob, Samson T.; Lawler, Sean E.; Kaur, Balveen; Baiocchi, Robert A.

doi:10.1158/0008-5472.can-13-0884

Cited by 139 publications

(129 citation statements)

References 39 publications

(56 reference statements)

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“…Several studies have found that PRMT5 is correlated with the progression of gliomas. For example, PRMT5 has been found overexpressed in glioma cells and associated with more aggressive disease in patients with glioblastoma [21]. In the same study, knockdown of PRMT5 has also been found lead to the down-regulation of Bcl-2 and up-regulation of Bax [21].…”

Section: Discussionmentioning

confidence: 99%

“…For example, PRMT5 has been found overexpressed in glioma cells and associated with more aggressive disease in patients with glioblastoma [21]. In the same study, knockdown of PRMT5 has also been found lead to the down-regulation of Bcl-2 and up-regulation of Bax [21]. In a recent study, PRMT5 has been found played a very significant role in glioblastoma neurospheres (GBMNS) self-renewal capacity and proliferation [22].…”

Section: Discussionmentioning

confidence: 99%

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LncRNA SNHG16 Functions as an Oncogene by Sponging MiR-4518 and Up-Regulating PRMT5 Expression in Glioma

Cai

et al. 2018

Cell Physiol Biochem

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Background/Aims: Long noncoding RNAs (lncRNAs) have recently emerged as novel and potentially promising therapeutic targets in various cancers. However, the expression pattern and biological function of lncRNAs in glioma remain largely elusive. In the present study, we investigated the functional role of an lncRNA, small nucleolar RNA host gene 16 (SNHG16), in glioma. Methods: The expression levels of SNHG16 and miR-4518 were measured using qRT-PCR. The relationship between the levels of SNHG16 and clinicopathologic features were statically analyzed. The levels of proteins were detected using western blot. Bioinformatics analysis and luciferase reporter assays were applied to the analysis of the relationship between SNHG16, miR-4518 and PRMT5. Cell viability and apoptosis were measured using MTT and apoptosis ELISA assay, respectively. Results: SNHG16 was highly expressed in glioma tissues and cell lines, which was related to poorer clinicopathologic features and shorter survival time. Knockdown of SNHG16 inhibits the viability and induces apoptosis of glioma cells. Further investigation revealed that SNHG16 could up-regulate the expression of miR-4518 targeted gene PRMT5 via acting as an endogenous sponge of miR-4518. Moreover, SNHG16 also affects the expression of Bcl-2 family proteins and the activation of PI3K/Akt signaling pathway. Conclusion: Our study revealed a novel SNHG16-miR-4518-PRMT5 pathway regulatory axis in glioma pathogenesis. SNHG16 could be used as a potential therapeutic target in the treatment of glioma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

LncRNA SNHG16 Functions as an Oncogene by Sponging MiR-4518 and Up-Regulating PRMT5 Expression in Glioma

Cai

et al. 2018

Cell Physiol Biochem

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“…The human genome encodes 11 PRMT isoforms that covalently modify arginine residues in histone and nonhistone proteins that contribute to diverse cellular regulatory networks (20). Types I and II PRMTs catalyse monomethylation at the ω-NH2 group of arginine; however, they differ in their ability to add the second methyl group, either asymmetrically (type I) or symmetrically (type II) (13,14,29). PRMT5 is a type II PRMT that catalyses the transfer of methyl groups from S-adenosyl methionine to the arginine residues of histones or non-histone proteins and is involved in numerous cellular processes (19,30).…”

Section: Discussionmentioning

confidence: 99%

Protein arginine methyltransferase 5 is associated with malignant phenotype and peritoneal metastasis in gastric cancer

Kanda

Shimizu

Fujii

et al. 2016

International Journal of Oncology

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Abstract. Identification of novel gastric cancer (GC)-related molecules is necessary to improve management of patients with GC in both diagnostic and therapeutic aspects. The aim of the present study was to determine whether protein arginine methyltransferase 5 (PRMT5) acts as an oncogene in the progression of GC and whether it serves as a novel diagnostic marker and therapeutic target. We conducted global expression profiling of GC cell lines and RNA interference experiments to evaluate the effect of PRMT5 expression on the phenotype of GC cells. We analysed tissues of 179 patients with GC to assess the association of PRMT5 mRNA levels with clinicopathological factors. Differential expression of PRMT5 mRNA by GC cell lines correlated positively with the levels of GEMIN2, STAT3 and TGFB3. PRMT5 knockdown reduced the proliferation, invasion and migration of a GC cell line. PRMT5 mRNA levels were significantly higher in GC tissues than the corresponding adjacent normal tissues and were independent of tumour depth, differentiation and lymph node metastasis. High PRMT5 expression was an independent risk factor of positive peritoneal lavage cytology (odds ratio 3.90, P=0.003) and decreased survival. PRMT5 enhances the malignant phenotype of GC cell lines and its expression in gastric tissues may serve as a biomarker for patient stratification and a potential target of therapy.

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“…Further supporting this notion, PRMT5-targeting siRNAs lead to cell-cycle arrest, apoptosis, and loss of cell migratory activity in glioblastoma cell lines, and increase survival in mice xenograft models of glioblastoma. 8 Similar to PRMT5, PRMT7 plays a role in the methylation of H3R2 as well as Sm proteins.…”

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confidence: 99%

Discovery of a Dual PRMT5–PRMT7 Inhibitor

Smil

Eram

et al. 2015

ACS Med. Chem. Lett.

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The protein arginine methyltransferases PRMT7 and PRMT5, respectively, monomethylate and symmetrically dimethylate arginine side-chains of proteins involved in diverse cellular mechanisms, including chromatin-mediated control of gene transcription, splicing, and the RAS to ERK transduction cascade. It is believed that PRMT5 and PRMT7 act in conjunction to methylate their substrates, and genetic deletions support the notion that these enzymes derepress cell proliferation and migration in cancer. Using available structures of PRMT5, we designed DS-437, a PRMT5 inhibitor with an IC 50 value of 6 μM against both PRMT5 and PRMT7 that is inactive against 29 other human protein-, DNA-, and RNA-methyltransferases and inhibits symmetrical dimethylation of PRMT5 substrates in cells. This compound behaves as a cofactor competitor and represents a valid scaffold to interrogate the potential of the PRMT5−PRMT7 axis as a target for therapy.KEYWORDS: PRMT5, PRMT7, inhibitor, methyltransferases P rotein arginine methyltransferases are a class of enzymes that transfer a methyl group from the cofactor Sadenosylmethionine (SAM) onto the arginine omega nitrogens of substrate proteins, including histones, and can be divided into three subclasses based on their product specificity: type I, II, and III PRMTs asymmetrically dimethylate, symmetrically dimethylate, and monomethylate their substrates, respectively. 1Of the nine confirmed human PRMTs, PRMT5 is currently the only known type II PRMT, and PRMT7 the only monomethylase.2,3 PRMT9 is uncharacterized, and other PRMTs are type I enzymes. 1 PRMT5 has been reported to methylate a number of substrates, both nuclear and cytoplasmic: methylation of arginine 3 of histone 4 (H4R3) by PRMT5 generates a binding site for DNMT3A and is associated with gene silencing; 4 PRMT5-mediated methylation of RAF proteins regulates the RAS to ERK signal transduction cascade and promotes cell proliferation; 5 methylation of Sm ribonucleoproteins (Sm) by PRMT5 mediates recruitment of SMN, and deletion of PRMT5 results in aberrant splicing/degradation of MDM4, associated with derepression of p53-mediated apoptosis. 6,7 These results suggest that PRMT5 may represent an attractive cancer target. Further supporting this notion, PRMT5-targeting siRNAs lead to cell-cycle arrest, apoptosis, and loss of cell migratory activity in glioblastoma cell lines, and increase survival in mice xenograft models of glioblastoma. 8Similar to PRMT5, PRMT7 plays a role in the methylation of H3R2 as well as Sm proteins.2,9 PRMT7 only monomethylates arginine side-chains 3 and interacts with PRMT5, suggesting that the two enzymes may function in conjunction to symmetrically dimethylate protein substrates.1 Genetic silencing of PRMT7 reduces symmetrical dimethylation of H4R3 (H4R3me2s), derepresses E-cadherin expression, and attenuates cell migration and invasion in breast cancer cells. 10 Potent, selective, and cell-active chemical probes targeting PRMT5 and PRMT7 would be useful tools to investigate molecular pathways, ...

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Genetic Validation of the Protein Arginine Methyltransferase PRMT5 as a Candidate Therapeutic Target in Glioblastoma

Cited by 139 publications

References 39 publications

LncRNA SNHG16 Functions as an Oncogene by Sponging MiR-4518 and Up-Regulating PRMT5 Expression in Glioma

LncRNA SNHG16 Functions as an Oncogene by Sponging MiR-4518 and Up-Regulating PRMT5 Expression in Glioma

Protein arginine methyltransferase 5 is associated with malignant phenotype and peritoneal metastasis in gastric cancer

Discovery of a Dual PRMT5–PRMT7 Inhibitor

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