This Article Full Text (PDF) Other Versions of this Article: MCB.00923-08v1 28/20/6262    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Google Scholar Articles by Wang, L. Articles by Sif, S. PubMed PubMed Citation Articles by Wang, L. Articles by Sif, S.

 Previous Article  |  Next Article 

Mol. Cell. Biol. doi:10.1128/MCB.00923-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

PRMT5 Suppresses the Transcription of the RB Family of Tumor Suppressors in Leukemia and Lymphoma Cells

Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio, 43210, USA

^* To whom correspondence should be addressed. Email: sif.1{at}osu.edu.

	Abstract

Proper epigenetic modification of chromatin by protein arginine methyltransferases (PRMTs) is crucial for normal cell growth and health. The hSWI/SNF-associated PRMT5 is involved in 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 altered expression of the PRMT5-specific miRNAs 19a, 25, 32, 92, 92b and 96, and results in increased global symmetric methylation of H3R8 and H4R3. Evaluation of both epigenetic marks at PRMT5 target genes such as RB1 (p105), RBL1 (p107) and RBL2 (p130) showed that promoter 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 transcription of key tumor suppressor genes, and suggest a causal role of elevated symmetric methylation of H3R8 and H4R3 at the RBL2 promoter in transformed B lymphocyte pathology.