Protein Arginine Methyltransferase 5 Suppresses the Transcription of the RB Family of Tumor Suppressors in Leukemia and Lymphoma Cells

Abstract

The proper epigenetic modification of chromatin by protein arginine methyltransferases (PRMTs) is crucial for normal cell growth and health. The human SWI/SNF-associated PRMT5 is involved in the transcriptional repression of target genes by directly methylating H3R8 and H4R3. To further understand the impact of PRMT5-mediated histone methylation on cancer, we analyzed its expression in normal and transformed human B lymphocytes. Our findings reveal that PRMT5 protein levels are enhanced in various human lymphoid cancer cells, including transformed chronic lymphocytic leukemia (B-CLL) cell lines. PRMT5 overexpression is caused by the altered expression of the PRMT5-specific microRNAs 19a, 25, 32, 92, 92b, and 96 and results in the increased global symmetric methylation of H3R8 and H4R3. An evaluation of both epigenetic marks at PRMT5 target genes such as RB1 (p105), RBL1 (p107), and RBL2 (p130) showed that promoters H3R8 and H4R3 are hypermethylated, which in turn triggers pocket protein transcriptional repression. Furthermore, reducing PRMT5 expression in WaC3CD5 B-CLL cells abolishes H3R8 and H4R3 hypermethylation, restores RBL2 expression, and inhibits cancer cell proliferation. These results indicate that PRMT5 overexpression epigenetically alters the transcription of key tumor suppressor genes and suggest a causal role of the elevated symmetric methylation of H3R8 and H4R3 at the RBL2 promoter in transformed B-lymphocyte pathology.Enzymes that modify chromatin via arginine methylation have different effects on gene expression, depending on whether they catalyze either the symmetric or asymmetric dimethylation of histones (20,31). Recent work has clearly established a link between the aberrant expression of chromatinmodifying enzymes and cancer; however, the impact protein arginine methyltransferases (PRMTs) have on cell growth and proliferation has only begun to be appreciated. The role PRMTs play in cancer epigenetics remains unexplored, and it is essential to unravel how histone arginine methylation influences cancer. Previous studies have shown that the expression of EZH2, the catalytic subunit of PRC2/3, is altered in cancer cells (19,32,40,41). Similarly, several reports have shown that the interplay and cross-talk between chromatin-modifying enzymes is necessary for the efficient regulation of gene expression, and that changes that affect the activity and/or targeting of chromatin remodelers can trigger cancer (13, 23).Histone methylation has emerged as an important epigenetic modification in the control of chromatin structure and gene expression, and there is little doubt that different epigenetic marks act either synergistically or antagonistically to specify transcriptional performance in various chromatin regions (13). The methylation of histones can be found on both lysine and arginine residues, and both modifications are introduced by SET and PRMT enzymes, respectively. Just like SET proteins, which either can induce or repress transcription, PRMTs either can induce or inhibit transcription depen...

miRNA-regulated expression of oncogenes and tumor suppressor genes in the cisplatin-inhibited growth of K562 cells

“…1B). BCL2, E2F1and E2F3 have oncogenic roles in tumor proliferation, while RB1 and P53 are tumor suppressor genes (11,12). These genes are common in tumor formation and therefore were chosen for study in K562 cells after cisplatin treatment.…”

Crystal structure of the human PRMT5:MEP50 complex

“…Protein methyltransferases are being actively pursued as drug targets for various types of cancer where enhanced levels of PRMT5 have been observed (4,(31)(32)(33). Despite the vital role played by PRMT5 in diverse cellular processes, and its potential as a drug target, there has been scant structural information on PRMT5 or its interaction with MEP50.…”

Novel Mechanism of Negative Regulation of 1,25-Dihydroxyvitamin D3-induced 25-Hydroxyvitamin D3 24-Hydroxylase (Cyp24a1) Transcription

“…The BRG1-based SWI/SNF complex containing PRMT5 has been found in association with the mSin3A-HDAC2 complex and is implicated in the repression of the MYC target gene cad (carbamoyl-phosphate synthase-aspartate carbamoyltransferase-dihydroorotase) (28). The PRMT5 SWI/SNF complex is also involved in transcriptional repression of ST7, NM23, and retinoblastoma-like protein 2 (RBL2) tumor suppressor genes (27,47). It has been suggested that SWI/SNFassociated PRMT5 is involved in silencing these genes through repressive histone marks including methylation of H3R8 and H4R3 (27,47).…”

“…The PRMT5 SWI/SNF complex is also involved in transcriptional repression of ST7, NM23, and retinoblastoma-like protein 2 (RBL2) tumor suppressor genes (27,47). It has been suggested that SWI/SNFassociated PRMT5 is involved in silencing these genes through repressive histone marks including methylation of H3R8 and H4R3 (27,47). In our study, we found that repression of 1,25(OH) 2 D 3 -induced Cyp24a1 transcription by PRMT5 involves recruitment of PRMT5 by BRG1, which is bound to C/EBP␤ at the C/EBP site, and at least in part symmetrical dimethylation of H3R8 and H4R3.…”