title: Protein arginine methyltransferase 5 (PRMT5) inhibition induces lymphoma cell death through reactivation of the retinoblastoma tumor suppressor pathway and polycomb repressor complex 2 (PRC2) silencing.
abstract: Epigenetic regulation mediated by lysine- and arginine-specific enzymes plays an essential role in tumorigenesis, and enhanced expression of the type II protein arginine methyltransferase PRMT5 as well as the polycomb repressor complex PRC2 has been associated with increased cell proliferation and survival. Here, we show that PRMT5 is overexpressed in three different types of non-Hodgkin lymphoma cell lines and clinical samples as well as in mouse primary lymphoma cells and that it up-regulates PRC2 expression through inactivation of the retinoblastoma proteins RB1 and RBL2. Although PRMT5 epigenetically controls RBL2 expression, it indirectly promotes RB1 phosphorylation through enhanced cyclin D1 expression. Furthermore, we demonstrate that PRMT5 knockdown in non-Hodgkin lymphoma cell lines and mouse primary lymphoma cells leads to RBL2 derepression and RB1 reactivation, which in turn inhibit PRC2 expression and trigger derepression of its CASP10, DAP1, HOXA5, and HRK pro-apoptotic target genes. We also show that reduced PRMT5 expression leads to cyclin D1 transcriptional repression via loss of TP53K372 methylation, which results in decreased BCL3 expression and enhanced recruitment of NF-κB p52-HDAC1 repressor complexes to the cyclin D1 promoter. These findings indicate that PRMT5 is a master epigenetic regulator that governs expression of its own target genes and those regulated by PRC2 and that its inhibition could offer a promising therapeutic strategy for lymphoma patients.
authors.affiliation: From the Departments Molecular and Cellular Biochemistry and.
authors.forename: Jihyun
authors.initials: J
authors.lastname: Chung
authors.forename: Vrajesh
authors.initials: V
authors.lastname: Karkhanis
authors.forename: Sookil
authors.initials: S
authors.lastname: Tae
authors.forename: Fengting
authors.initials: F
authors.lastname: Yan
authors.forename: Porsha
authors.initials: P
authors.lastname: Smith
authors.forename: Leona W
authors.initials: LW
authors.lastname: Ayers
authors.forename: Claudio
authors.initials: C
authors.lastname: Agostinelli
authors.forename: Stefano
authors.initials: S
authors.lastname: Pileri
authors.forename: Gerald V
authors.initials: GV
authors.lastname: Denis
authors.forename: Robert A
authors.initials: RA
authors.lastname: Baiocchi
authors.forename: Saïd
authors.initials: S
authors.lastname: Sif
mesh_terms: D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D044127:Epigenesis, Genetic; D055785:Gene Knockdown Techniques; D016161:Genes, Retinoblastoma; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: C530104:CCND1 protein, human; C530105:Ccnd1 protein, mouse; C493837:RBL2 protein, human; C493838:Rbl2 protein, mouse; D016160:Retinoblastoma Protein; D050717:Retinoblastoma-Like Protein p130; D019938:Cyclin D1; D011496:Protein Methyltransferases; C400529:PRMT5 protein, human; C498518:Prmt5 protein, mouse; D011484:Protein-Arginine N-Methyltransferases; D063151:Polycomb Repressive Complex 2; C533423:HDAC2 protein, human; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2
keywords: Chromatin Histone Modification; Cyclin D1; Leukemia; Lymphoma; PRC2; PRMT5; RB1; RBL2; Retinoblastoma (Rb)