Document Type
Article
Publication Date
7-8-2022
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.
Recommended Citation
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.; and Wu, Qiong, "PRMT5 activates AKT via methylation to promote tumor metastasis." (2022). Department of Pediatrics Faculty Papers. Paper 118.
https://jdc.jefferson.edu/pedsfp/118
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
35803962
Language
English
Comments
This is the final published version of the article from Nature Communications, 2022 Jul 8;13(1):3955.
The article can also be accessed on the journal's website: https://doi.org/10.1038/s41467-022-31645-1
Copyright. The Authors.