PRMT5 activates AKT via methylation to promote tumor metastasis

• Published in: Nature communications Vol. 13; no. 1; p. 3955
• Main Authors: Huang, Lei, Zhang, Xiao-Ou, Rozen, Esteban J., Sun, Xiaomei, Sallis, Benjamin, Verdejo-Torres, Odette, Wigglesworth, Kim, Moon, Daniel, Huang, Tingting, Cavaretta, John P., Wang, Gang, Zhang, Lei, Shohet, Jason M., Lee, Mary M., Wu, Qiong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08-07-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/2; 13/31; 13/95; 14/1; 14/19; 38/70; 38/79; 59/5; 631/67/2332; 631/67/322; 64/60; 692/699/67; AKT protein; AKT1 protein; Arginine; Downstream effects; Gene expression; Health risks; Histones; Humanities and Social Sciences; Kinases; Mesenchyme; Metastases; Metastasis; Methylation; multidisciplinary; Neuroblastoma; Organs; Phosphorylation; Protein arginine methyltransferase; Proteins; Science; Science (multidisciplinary); Snail protein; Transcription factors; Translocation; Tumors; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31645-1

Protein arginine methyltransferase 5 (PRMT5) is the primary methyltransferase generating symmetric-dimethyl-arginine marks on histone and non-histone proteins. PRMT5 dysregulation is implicated in multiple oncogenic processes. Here, we report that PRMT5-mediated methylation of protein kinase B (AKT) is required for its subsequent phosphorylation at Thr308 and Ser473. Moreover, pharmacologic or genetic inhibition of PRMT5 abolishes AKT1 arginine 15 methylation, thereby preventing AKT1 translocation to the plasma membrane and subsequent recruitment of its upstream activating kinases PDK1 and mTOR2. We show that PRMT5/AKT signaling controls the expression of the epithelial-mesenchymal-transition transcription factors ZEB1, SNAIL, and TWIST1. PRMT5 inhibition significantly attenuates primary tumor growth and broadly blocks metastasis in multiple organs in xenograft tumor models of high-risk neuroblastoma. Collectively, our results suggest that PRMT5 inhibition augments anti-AKT or other downstream targeted therapeutics in high-risk metastatic cancers.
‘Protein arginine methyltransferase 5 (PRMT5) is known to regulate the expression of genes involved in metastasis. Here, the authors show that PRMT5 methylates Akt and methylation is required for phosphorylation and activation of Akt; ultimately leading to the increase in expression of pro-metastatic transcription factors.