Show simple item record

AuthorChung, Jihyun
AuthorKarkhanis, Vrajesh
AuthorBaiocchi, Robert A.
AuthorSif, Said
Available date2020-08-12T09:32:59Z
Publication Date2019
Publication NameJournal of Biological Chemistry
ResourceScopus
URIhttp://dx.doi.org/10.1074/jbc.RA119.007640
URIhttp://hdl.handle.net/10576/15513
AbstractEpigenetic regulation by the type II protein arginine methyltransferase, PRMT5, plays an essential role in the control of cancer cell proliferation and tumorigenesis. In this report, we investigate the relationship between PRMT5 and WNT/B- CATENIN as well as AKT/GSK3B proliferative signaling in three different types of non-Hodgkin's lymphoma cell lines, clinical samples, and mouse primary lymphoma cells. We show that PRMT5 stimulates WNT/B-CATENIN signaling through direct epigenetic silencing of pathway antagonists, AXIN2 and WIF1, and indirect activation of AKT/GSK3 signaling.PRMT5 inhibition with either shRNA-mediated knockdown or a specific small molecule PRMT5 inhibitor, CMP-5, not only leads to derepression of WNT antagonists and decreased levels of active phospho-AKT (Thr-450 and Ser-473) and inactive phospho- GSK3B (Ser-9) but also results in decreased transcription of WNT/B-CATENIN target genes, CYCLIN D1, c-MYC, and SURVIVIN, and enhanced lymphoma cell death. Furthermore, PRMT5inhibition leads to reduced recruitment of co-activators CBP, p300, and MLL1, as well as enhanced recruitment of co-repressors HDAC2 and LSD1 to the WNT/B-CATENIN target gene promoters. These results indicate that PRMT5 governs expression of prosurvival genes by promoting WNT/B- CATENIN and AKT/GSK3 proliferative signaling and that its inhibition induces lymphoma cell death, which warrants further clinical evaluation.
SponsorThis work was supported by Leukemia and Lymphoma Society Award MCL7001-18 (to R. A. B.) and National Priorities Research Program Grant NPRP8-617-3-131 from the National Research Fund (a member of Qatar Foundation) (to S. S).
Languageen
PublisherAmerican Society for Biochemistry and Molecular Biology Inc.
SubjectProtein arginine methyltransferase 5 (PRMT5)
TitleProtein arginine methyltransferase 5 (PRMT5) promotes survival of lymphoma cells via activation of WNT/B-catenin and AKT/GSK3B proliferative signaling
TypeArticle
Pagination7692-7710
Issue Number19
Volume Number294
dc.accessType Abstract Only


Files in this item

FilesSizeFormatView

There are no files associated with this item.

This item appears in the following Collection(s)

Show simple item record