PRMT5 activates AKT via methylation to promote tumor metastasis

Lei Huang, Xiao-Ou Zhang, Esteban J. Rozen, Xiaomei Sun, Benjamin Sallis, Odette Verdejo-Torres, Kim Wigglesworth, Daniel Moon, Tingting Huang, John P. Cavaretta, Gang Wang, Lei Zhang, Jason M. Shohet, Mary M. Lee () and Qiong Wu ()
Additional contact information
Lei Huang: University of Massachusetts Chan Medical School
Xiao-Ou Zhang: University of Massachusetts Chan Medical School
Esteban J. Rozen: University of Massachusetts Chan Medical School
Xiaomei Sun: University of Massachusetts Chan Medical School
Benjamin Sallis: University of Massachusetts Chan Medical School
Odette Verdejo-Torres: University of Massachusetts Chan Medical School
Kim Wigglesworth: University of Massachusetts Chan Medical School
Daniel Moon: Tufts University
Tingting Huang: University of Massachusetts Chan Medical School
John P. Cavaretta: University of Massachusetts Chan Medical School
Gang Wang: University of Massachusetts Chan Medical School
Lei Zhang: University of Massachusetts Chan Medical School
Jason M. Shohet: University of Massachusetts Chan Medical School
Mary M. Lee: Thomas Jefferson University
Qiong Wu: University of Massachusetts Chan Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-31645-1

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