The dual epigenetic role of PRMT5 in acute myeloid leukemia: gene activation and repression via histone arginine methylation
Open accessAbstract
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.
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Specific inhibitors of PRMT5 have recently entered early stage clinical trials.
“on the back of these data specific inhibitors of PRMT5 have recently entered early stage clinical trials 179 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [179]
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- Authors
- Tarighat, S. S., Santhanam, R., Frankhouser, D., Radomska, H. S., Lai, H., Anghelina, M., Wang, H., Huang, X., Alinari, L., Walker, A., Caligiuri, M. A., Croce, C. M., Li, L., Garzon, R., Li, C., Baiocchi, R. A., & Marcucci, G.
- Affiliations
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- The Ohio State University (US)
- City Of Hope National Medical Center (US)
- Corresponding author
- Marcucci, G
- ORCID
- Venue
- Leukemia
- Published
- 2015-11-05
- Volume
- 30
- Issue
- 4
- Pages
- 789-799
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- PMC
- PMC8034866
- OpenAlex
- W2183418069
- Cited by
- 169
- References
- 47
- Citations by year
- 2026: 5 · 2025: 17 · 2024: 13 · 2023: 19 · 2022: 17 · 2021: 17 · 2020: 17 · 2019: 21 · 2018: 14 · 2017: 20 · 2016: 8
- FWCI
- 6.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Leukemia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50CA140158, R01-CA140158, P30CA016058)
- National Institute of Neurological Disorders and Stroke (R21NS071346)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- PRMT5, acute myeloid leukemia, histone arginine methylation, Sp1, miR-29b, FLT3, transcriptional repression, transcriptional activation, protein arginine methyltransferase, therapeutic target
- MeSH terms
- Animals, Arginine, Flow Cytometry, Histones, Humans, Immunoenzyme Techniques, Protein-Arginine N-Methyltransferases, RNA, Messenger, Tumor Cells, Cultured, Blotting, Western, Leukemia, Myeloid, Acute, Transcriptional Activation, Down-Regulation, Gene Expression Regulation, Leukemic, Mice, SCID, Mice, Inbred NOD, Apoptosis, DNA Methylation, Reverse Transcriptase Polymerase Chain Reaction, Xenograft Model Antitumor Assays, RNA, Small Interfering, MicroRNAs, Epigenesis, Genetic, Chromatin Immunoprecipitation, Cell Proliferation, Mice, Epigenomics, Real-Time Polymerase Chain Reaction
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