title: The dual epigenetic role of PRMT5 in acute myeloid leukemia: gene activation and repression via histone arginine methylation.
abstract: Changes in the enzymatic activity of protein arginine methyltransferase (PRMT) 5 have been associated with cancer; however, the protein's role in acute myeloid leukemia (AML) has not been fully evaluated. Here, we show that increased PRMT5 activity enhanced AML growth in vitro and in vivo while PRMT5 downregulation reduced it. In AML cells, PRMT5 interacted with Sp1 in a transcription repressor complex and silenced miR-29b preferentially via dimethylation of histone 4 arginine residue H4R3. As Sp1 is also a bona fide target of miR-29b, the miR silencing resulted in increased Sp1. This event in turn led to transcription activation of FLT3, a gene that encodes a receptor tyrosine kinase. Inhibition of PRMT5 via sh/siRNA or a first-in-class small-molecule inhibitor (HLCL-61) resulted in significantly increased expression of miR-29b and consequent suppression of Sp1 and FLT3 in AML cells. As a result, significant antileukemic activity was achieved. Collectively, our data support a novel leukemogenic mechanism in AML where PRMT5 mediates both silencing and transcription of genes that participate in a 'yin-yang' functional network supporting leukemia growth. As FLT3 is often mutated in AML and pharmacologic inhibition of PRMT5 appears feasible, the PRMT5-miR-29b-FLT3 network should be further explored as a novel therapeutic target for AML.
authors.affiliation: Molecular, Cellular, and Developmental Biology Graduate Program, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Tarighat
authors.affiliation: Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Santhanam
authors.affiliation: Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: D
authors.initials: D
authors.lastname: Frankhouser
authors.affiliation: Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: H S
authors.initials: HS
authors.lastname: Radomska
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: H
authors.initials: H
authors.lastname: Lai
authors.affiliation: Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Anghelina
authors.affiliation: Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: Molecular, Cellular, and Developmental Biology Graduate Program, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.affiliation: Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: L
authors.initials: L
authors.lastname: Alinari
authors.affiliation: Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Walker
authors.affiliation: Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: Department of Molecular Virology, Immunology and Cancer Genetics, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Gehr Family Leukemia Center, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Garzon
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.affiliation: Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Baiocchi
authors.affiliation: Gehr Family Leukemia Center, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Marcucci
mesh_terms: D000818:Animals; D017209:Apoptosis; D001120:Arginine / Q000737:chemistry*; D015153:Blotting, Western; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic / Q000235:genetics*; D057890:Epigenomics; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D006657:Histones / Q000737:chemistry*; D006801:Humans; D007124:Immunoenzyme Techniques; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D006657:Histones; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D001120:Arginine; C413164:PRMT3 protein, human; D011484:Protein-Arginine N-Methyltransferases