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Protein arginine-methyltransferase-dependent oncogenesis

Nature Cell Biology volume 9, pages 1208–1215 (2007)Cite this article

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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Figure 1: The EEN-SH3 domain is necessary and sufficient for MLL–EEN-mediated transformation.
Figure 2: Identification of the protein complexes associated with the EEN-SH3 domain.
Figure 3: MLL–EEN mediates histone acetylation and H4R3 methylation on the Hoxa9 promoter, and enhances its expression.
Figure 4: The role of Sam68 in MLL–EEN-mediated transformation of primary haematopoietic cells.
Figure 5: The role of PRMT1 in MLL–EEN-mediated transformation of primary haematopoietic cells.

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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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Authors and Affiliations

  1. Haemato-Oncology Section, The Institute of Cancer Research, Sutton, Greater London, SM2 5NG, UK

    Ngai Cheung & Chi Wai Eric So

  2. Department of Pathology, The University of Hong Kong, Hong Kong

    Li Chong Chan

  3. Department of Haematology, Queen's University, Belfast, BT9 7AB, Northern Ireland

    Alex Thompson

  4. Department of Pathology, Stanford University Medical Center, Stanford, 93405, CA, USA

    Michael L Cleary

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  1. Ngai Cheung
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  2. Li Chong Chan
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Contributions

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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Correspondence to Chi Wai Eric So.

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Supplementary figures S1, S2, S3 and S4 (PDF 160 kb)

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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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