Aging, Environment, & DiseaseHistone Modifications

When the writing is wrong: PRMT5 histone arginine methylation promotes invasivity and metastasis in a range of human cancers

When the writing is wrong: PRMT5 histone methylation promotes invasivity and metastasis in a range of human cancersCancer metastasis occurs when cancer cells leave a primary tumor and invade other tissues. Generally, this leads to a poor prognosis for patients. Underlying epigenetic mechanisms of tumor progression are poorly understood but are of great interest for developing new approaches of treatment in the clinic. Cancer etiology is highly correlated with alterations in the histone code1-5 and protein methyltransferases are frequently dysregulated in cancer, implicating them as compelling novel targets for chemotherapy. Arginine methylation in particular regulates biological function3,6,7 as well as oncogenesis and tumor progression.1,2,6 The protein arginine methyltransferases (PRMT) family targets a range of substrates, including histones, spliceosomal factors, and ribosomal proteins.9-11 Recent reports have linked the dysregulation of arginine methylation to numerous cancers and our recent paper Chen et al. investigates the role of PRMT5, a histone arginine methyltransferase, in cancer metastasis and tumor progression.

PRMT5 function requires its essential cofactor MEP50/WDR77. In cancer cells, PRMT5-MEP50 activity is elevated and increased expression of the protein complex correlates with tumor progression and poor prognosis.3,12,13 In a new study,14 my laboratory and colleagues at the Albert Einstein College of Medicine, Bronx, NY, show that TGFβ signaling induces metastasis in lung and breast cancer cells15 in part by increasing PRMT5 methylation of histones which results in altered expression of key genes involved in making cancer cells invasive. Exogenous TGFb promotes the epithelial-to-mesenchymal transition (EMT)16 in a unique pathway of PRMT5-MEP50 catalyzed histone mono- and dimethylation of chromatin at key metastasis suppressor and EMT genes, defining a new mechanism regulating cancer invasivity. We show that PRMT5 methylation of histone H3R2me1 induces transcriptional activation by recruitment of WDR5 as well as H3K4 methylation at targeted genes. In parallel, PRMT5 methylation of H4R3me2s suppressed transcription at distinct genomic loci. This conclusively demonstrates that PRMT5-MEP50 activity both positively and negatively regulates expression of a wide range of genes, one of only few examples of simultaneous up-and-down regulation of gene expression, especially in concise biological pathways.

Importantly for potential human clinical application, we show that the cancer-promoting activity of PRMT5 can be blocked by GSK591, a potent inhibitory compound developed by Epizyme and GSK and distributed by The Structural Genomics Consortium.12 Taking advantage of RNA-Seq transcriptome analysis (dataset here), we demonstrated that PRMT5 and MEP50 are required to maintain expression of metastasis and EMT markers and may underlie an epigenetic mechanism of the TGFb response.

In summary, we demonstrate that PRMT5-MEP50 activity is essential for transcriptional changes which promote cancer cell invasive phenotypes in lung adenocarcinoma, lung squamous cell carcinoma and breast carcinoma cancer cells. Our study links TGFβ and PRMT5 for the first time, and the decoding of histone methylarginine at key genes supports a critical role for complementary PRMT5-MEP50 transcriptional activation and repression in cancer invasion pathways.  Future chemotherapeutic opportunities and possible new cancer metastasis treatment strategies are an exciting possibility for clinical outcomes of this work. Our study was published in  June 2016 in Oncogene.

 

Original Article:
Chen H, Lorton B, Gupta V, & Shechter D (2016). A TGFβ-PRMT5-MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repression. Oncogene PMID: 27270440
References:
1. Chi P, Allis CD, & Wang GG (2010). Covalent histone modifications–miswritten, misinterpreted and mis-erased in human cancers. Nature reviews. Cancer, 10 (7), 457-69 PMID: 20574448
2. Sawan, Carla (2010). Histone Modifications and Cancer Adv Genet, 57-85 DOI: 10.1016/B978-0-12-380866-0.60003-4
3. Stopa N, Krebs JE, & Shechter D (2015). The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond. Cellular and molecular life sciences : CMLS, 72 (11), 2041-59 PMID: 25662273
4. Cha B, & Jho EH (2012). Protein arginine methyltransferases (PRMTs) as therapeutic targets. Expert opinion on therapeutic targets, 16 (7), 651-64 PMID: 22621686
5. Sebova K, & Fridrichova I (2010). Epigenetic tools in potential anticancer therapy. Anti-cancer drugs, 21 (6), 565-77 PMID: 20436342
6. Yang, Y., & Bedford, M. (2012). Protein arginine methyltransferases and cancer Nature Reviews Cancer, 13 (1), 37-50 DOI: 10.1038/nrc3409
7. Yang XJ, & Seto E (2008). Lysine acetylation: codified crosstalk with other posttranslational modifications. Molecular cell, 31 (4), 449-61 PMID: 18722172
8. Greenblatt SM, Liu F, & Nimer SD (2016). Arginine methyltransferases in normal and malignant hematopoiesis. Experimental hematology, 44 (6), 435-41 PMID: 27026282
9. Wilczek C, Chitta R, Woo E, Shabanowitz J, Chait BT, Hunt DF, & Shechter D (2011). Protein arginine methyltransferase Prmt5-Mep50 methylates histones H2A and H4 and the histone chaperone nucleoplasmin in Xenopus laevis eggs. The Journal of biological chemistry, 286 (49), 42221-31 PMID: 22009756
10. Ho MC, Wilczek C, Bonanno JB, Xing L, Seznec J, Matsui T, Carter LG, Onikubo T, Kumar PR, Chan MK, Brenowitz M, Cheng RH, Reimer U, Almo SC, & Shechter D (2013). Structure of the arginine methyltransferase PRMT5-MEP50 reveals a mechanism for substrate specificity. PloS one, 8 (2) PMID: 23451136
11. Burgos ES, Wilczek C, Onikubo T, Bonanno JB, Jansong J, Reimer U, & Shechter D (2015). Histone H2A and H4 N-terminal tails are positioned by the MEP50 WD repeat protein for efficient methylation by the PRMT5 arginine methyltransferase. The Journal of biological chemistry, 290 (15), 9674-89 PMID: 25713080
12. Chan-Penebre E, Kuplast KG, Majer CR, Boriack-Sjodin PA, Wigle TJ, Johnston LD, Rioux N, Munchhof MJ, Jin L, Jacques SL, West KA, Lingaraj T, Stickland K, Ribich SA, Raimondi A, Scott MP, Waters NJ, Pollock RM, Smith JJ, Barbash O, Pappalardi M, Ho TF, Nurse K, Oza KP, Gallagher KT, Kruger R, Moyer MP, Copeland RA, Chesworth R, & Duncan KW (2015). A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nature chemical biology, 11 (6), 432-7 PMID: 25915199
13. Liu F, Cheng G, Hamard PJ, Greenblatt S, Wang L, Man N, Perna F, Xu H, Tadi M, Luciani L, & Nimer SD (2015). Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis. The Journal of clinical investigation, 125 (9), 3532-44 PMID: 26258414
14. Chen H, Lorton B, Gupta V, & Shechter D (2016). A TGFβ-PRMT5-MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repression. Oncogene PMID: 27270440
15. Ikushima H, & Miyazono K (2010). TGFbeta signalling: a complex web in cancer progression. Nature reviews. Cancer, 10 (6), 415-24 PMID: 20495575
16. Lamouille, S., Xu, J., & Derynck, R. (2014). Molecular mechanisms of epithelial–mesenchymal transition Nature Reviews Molecular Cell Biology, 15 (3), 178-196 DOI: 10.1038/nrm3758

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David Shechter

David Shechter