PRMT7 Induces Epithelial-to-Mesenchymal Transition and Promotes Metastasis in Breast Cancer

Yao, Ruosi; Jiang, Hao; Ma, Yanju; Wang, Liping; Du, Juan; Hou, Pingfu; Gao, Yanyan; Zhao, Li; Wang, Guannan; Zhang, Yu; Liu, Dong-Xu; Huang, Baiqu; Lü, Jun

doi:10.1158/0008-5472.can-14-0800

Cited by 116 publications

(131 citation statements)

References 49 publications

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“…10 The reduction of symmetrical arginine dimethylation of SmD1/3 and SmB proteins in breast cancer cells upon treatment with DS-437 is consistent with the cellular effect of PRMT5 and PRMT7 knockout/downs. PRMT5 and PRMT7 have also been found to cooperate in methylating H3R2.…”

Section: Acs Medicinal Chemistry Letterssupporting

confidence: 60%

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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Section: Acs Medicinal Chemistry Letterssupporting

confidence: 60%

Discovery of a Dual PRMT5–PRMT7 Inhibitor

Smil

Eram

et al. 2015

ACS Med. Chem. Lett.

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“…The emerging role of PRMTs in cancer (4,5,34,35) has profoundly spurred the research into PRMT inhibitors (36). One of the major issues in this field, however, has been the promiscuity of many PRMT inhibitors derived from small molecule library screening (37).…”

Section: Discussionmentioning

confidence: 99%

Protein Arginine Methyltransferase Product Specificity Is Mediated by Distinct Active-site Architectures

Jain¹,

Warmack²,

Debler³

et al. 2016

Journal of Biological Chemistry

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In the family of protein arginine methyltransferases (PRMTs) that predominantly generate either asymmetric or symmetric dimethylarginine (SDMA), PRMT7 is unique in producing solely monomethylarginine (MMA) products. The type of methylation on histones and other proteins dictates changes in gene expression, and numerous studies have linked altered profiles of methyl marks with disease phenotypes. Given the importance of specific inhibitor development, it is crucial to understand the mechanisms by which PRMT product specificity is conferred. We have focused our attention on active-site residues of PRMT7 from the protozoan Trypanosoma brucei. We have designed 26 single and double mutations in the active site, including residues in the Glu-Xaa 8 -Glu (double E) loop and the Met-Gln-Trp sequence of the canonical Thr-His-Trp (THW) loop known to interact with the methyl-accepting substrate arginine. Analysis of the reaction products by high resolution cation exchange chromatography combined with the knowledge of PRMT crystal structures suggests a model where the size of two distinct subregions in the active site determines PRMT7 product specificity.

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“…It plays a key role in embryonic development, and its importance in the pathogenesis of cancer invasion has been recognized as important [5]. Studies indicate that EMT plays a critical role in cancer metastatic progression [6][7][8], including in HCC [9]. The function of EMT in metastasis is the downregulation of epithelial markers, such as E-cadherin, and induction of the expression of mesenchymal markers, such as N-cadherin and vimentin.…”

Section: Introductionmentioning

confidence: 99%