Low levels of miR-92b/96 induce PRMT5 translation and H3R8/H4R3 methylation in mantle cell lymphoma

Abstract

Protein arginine methyltransferase PRMT5 interacts with human SWI/SNF complexes and methylates histones H3R8 and H4R3. To elucidate the role of PRMT5 in human cancer, we analyzed PRMT5 expression in normal human B lymphocytes and a panel of lymphoid cancer cell lines as well as mantle cell lymphoma (MCL) clinical samples. We show that PRMT5 protein levels are elevated in all cancer cells, including clinical samples examined despite its low rate of transcription and messenger RNA stability. Remarkably, polysome profiling revealed that PRMT5 mRNA is translated more efficiently in Mino and JeKo MCL cells than in normal B cells, and that decreased miR-92b and miR-96 expression augments PRMT5 translation. Consequently, global methylation of H3R8 and H4R3 is increased and is accompanied by repression of suppressor of tumorigenecity 7 (ST7) in lymphoid cancer cells. Furthermore, knockdown of PRMT5 expression reduces proliferation of transformed JeKo and Raji cells. Thus, our studies indicate that aberrant expression of PRMT5 leads to altered epigenetic modification of chromatin, which in turn impacts transcriptional performance of anti-cancer genes and growth of transformed lymphoid cells.

PRMT5, a Novel TRAIL Receptor-Binding Protein, Inhibits TRAIL-Induced Apoptosis via Nuclear Factor-κB Activation

“…These findings by Pal et al suggest that PRMT5 regulates cell proliferation by controlling expression of genes involved in tumor suppression. These investigators recently revealed that low levels of particular micro-RNA induce PRMT5 translation in human lymphoma (29). PRMT5 proteins were elevated in lymphoma cells over normal B lymphocytes.…”

“…PRMT5 is one of the evolutionarily conserved type II arginine methyltransferases that catalyze monomethylation and symmetric dimethylation (26,27). Expression of PRMT5 is ubiquitous among various tissues and is elevated in gastric cancer and lymphoma (28,29). In addition, overexpression of PRMT5 promoted transformation of NIH3T3 cells, suggesting its role in tumor progression (30).…”

Histone Arginine Methylation by PRMT7 Controls Germinal Center Formation via Regulating Bcl6 Transcription

“…Previously, we reported that arginine methylation was associated with B cell leukemia; another two reports also provided data on roles during B cell development and lymphoma genesis (29)(30)(31). Given that histone arginine methylation was a common posttranslation modification and that arginine methylation deficiency by PRMTs knockout in mice led to abnormal development (14), we generated PRMT7-knockout mice by gene targeting (Supplemental Fig.…”

In situ histone landscape of nephrogenesis

“…17 H3R2me2s is a repressive histone modification, 33,34 whereas and H3R8me2as may mediate either activation or repression. [35][36][37] H3R17me2as is generally an activating mark. 38,39 Interestingly, there was a differential enrichment of these three histone marks, since H3R2me2 and H3R17me2 are abundantly expressed in the cap mesenchyme and nascent nephrons, whereas H3R8me2 is more enriched in nascent nephrons (Fig.…”