Protein arginine methyltransferase 5 promotes metastasis via enhancing EGFR transcription and modulating AKT1 activation by methylation

Huang, L.; Zhang, X.-O.; Verdejo-Torres, O.; Wigglesworth, K.; Sun, X.; Sallis, B.; Moon, D.; Huang, T.; Rozen, E.; Zhang, L.; Wang, G.; Shohet, J. M.; Lee, M. M.; Wu, J. Q.

doi:10.1101/2020.08.12.246660

bioRxiv · 10.1101/2020.08.12.246660

Protein arginine methyltransferase 5 promotes metastasis via enhancing EGFR transcription and modulating AKT1 activation by methylation

Huang, L.·Zhang, X.-O.·Verdejo-Torres, O.·Wigglesworth, K.·Sun, X.·Sallis, B.·Moon, D.·Huang, T.·Rozen, E.·Zhang, L.·Wang, G.·Shohet, J. M.·Lee, M. M.·Wu, J. Q.

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Abstract

Protein arginine methyltransferase 5 (PRMT5) regulates a wide range of physiological processes, including cancer cell proliferation and metastasis, by generating symmetric di-methyl-arginine marks on histones and non-histone proteins. Here, we report that PRMT5 directly regulates epidermal growth factor receptor (EGFR) transcription to control EGF stimulated EGFR signaling. Furthermore, PRMT5 modulates protein kinase B (AKT) activation by methylation of AKT1 Arg 15, which is required for its subsequent phosphorylation at AKT1 Thr 308 and Ser 473. The PRMT5/EGFR/AKT axis converges to regulate transcription factors ZEB1, SNAIL, and TWIST1 to promote the epithelial-mesenchymal transition (EMT), in the manner that EGFR and AKT1 compensate each other to support tumor cell invasion and metastasis. Inhibiting PRMT5 methyltransferase activity with a small molecule inhibitor attenuated primary tumor growth and prevented hepatic metastasis in aggressive in vivo tumor models. Collectively, our results support the use of PRMT5 based therapies for metastatic cancer.

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Huang, L., Zhang, X.-O., Verdejo-Torres, O., Wigglesworth, K., Sun, X., Sallis, B., Moon, D., Huang, T., Rozen, E., Zhang, L., Wang, G., Shohet, J. M., Lee, M. M., Wu, J. Q.. 2020-08-13. Protein arginine methyltransferase 5 promotes metastasis via enhancing EGFR transcription and modulating AKT1 activation by methylation. https://doi.org/10.1101/2020.08.12.246660

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