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Sumoylation of MEL1S at lysine 568 and its interaction with CtBP facilitates its repressor activity and the blockade of G-CSF-induced myeloid differentiation

Oncogene volume 30, pages 4194–4207 (2011)Cite this article

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Abstract

MEL1 (MDS1/EVI1-like gene 1/PRDM16), which was identified as a gene near the chromosomal breakpoint in t(1;3)(p36;q21)-positive human acute myeloid leukemia cells, belongs to the PRDI-BF1-RIZ1 homologous (PR) domain (PRDM) family of transcription repressors. The short form of MEL1 (MEL1S), which lacks the PR-domain at the N-terminus, is the main form expressed in t(1;3)(p36;q21)-positive acute myeloid leukemia cells. The overexpression of MEL1S blocks granulocyte colony-stimulating factor (G-CSF)-induced myeloid differentiation in interleukin-3-dependent murine myeloid L-G3 cells. In this study, we show that treatment with the histone deacetylase inhibitor trichostatin A abolished the blockade of myeloid differentiation in L-G3 cells overexpressing MEL1S. The expression of MEL1S containing mutated CtBP-interacting motif (CIM) in L-G3 cells still blocked the myeloid differentiation induced by G-CSF. We found that the small ubiquitin-related modifier (SUMO) motif (SM) at lysine 568 (VKAE) adjacent to the CIM was necessary to obtain the maximum transcriptional repressor activity of MEL1S. L-G3 cells expressing MEL1S, and bearing mutated CIM and SM differentiated into granulocytes in response to G-CSF; this indicated that both the SUMO modification at lysine 568 and CtBP binding were required for MEL1S-mediated transcriptional repression and blockade of differentiation, which might be relevant for the process of leukemogenesis.

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Acknowledgements

This work was supported in part by Grants-in-Aid for Scientific Research of Priority Area from the Ministry of Education, Culture, Sports, Science and Technology in Japan.

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  1. Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

    I Nishikata, S Nakahata, Y Saito, K Kaneda, E Ichihara, N Yamakawa & K Morishita

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  1. I Nishikata
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  2. S Nakahata
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Correspondence to K Morishita.

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Nishikata, I., Nakahata, S., Saito, Y. et al. Sumoylation of MEL1S at lysine 568 and its interaction with CtBP facilitates its repressor activity and the blockade of G-CSF-induced myeloid differentiation. Oncogene 30, 4194–4207 (2011). https://doi.org/10.1038/onc.2011.132

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