Abstract
Enzymes that mediate reversible epigenetic modifications have not only been recognized as key in regulating gene expression1 and oncogenesis2,3, but also provide potential targets for molecular therapy4. Although the methylation of arginine 3 of histone 4 (H4R3) by protein arginine methyltransferase 1 (PRMT1) is a critical modification for active chromatin5,6 and prevention of heterochromatin spread7, there has been no direct evidence of any role of PRMTs in cancer. Here, we show that PRMT1 is an essential component of a novel Mixed Lineage Leukaemia (MLL) oncogenic transcriptional complex with both histone acetylation and H4R3 methylation activities, which also correlate with the expression of critical MLL downstream targets. Direct fusion of MLL with PRMT1 or Sam68, a bridging molecule in the complex for PRMT1 interaction, could enhance self-renewal of primary haematopoietic cells. Conversely, specific knockdown of PRMT1 or Sam68 expression suppressed MLL-mediated transformation. This study not only functionally dissects the oncogenic transcriptional machinery associated with an MLL fusion complex, but also uncovers — for the first time — an essential function of PRMTs in oncogenesis and reveals their potential as novel therapeutic targets in human cancer.
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Acknowledgements
We thank M. Greaves, P. Workman, A. Ashworth, T. Lappin, S. Armstrong, A. Zelent, S. Huang and D. Shuo for useful discussion; J. Yam, G. McGonigle, B. Zeisig, W. Yue, A. Wilson, M. Boix-Chornet for excellent technical help; A. Thornhill, F. Darling, BSU staff for husbandry of mice; and P. Tse for professional artwork. This work is supported by the Association for International Cancer Research (AICR), and CWE So is an AICR research fellow.
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N.C. performed most of the experiments; A.T. did the Q–RT–QPCR; L.C.C. and M.L.C. provided critical advice; C.W.E.S. designed and oversaw the project and wrote the manuscript.
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Cheung, N., Chan, L., Thompson, A. et al. Protein arginine-methyltransferase-dependent oncogenesis. Nat Cell Biol 9, 1208–1215 (2007). https://doi.org/10.1038/ncb1642
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DOI: https://doi.org/10.1038/ncb1642
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