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OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors

Oncogene volume 36, pages 1911–1924 (2017)Cite this article

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Abstract

MYC genes have both essential roles during normal development and exert oncogenic functions during tumorigenesis. Expression of a dominant-negative allele of MYC, termed OmoMYC, can induce rapid tumor regression in mouse models with little toxicity for normal tissues. How OmoMYC discriminates between physiological and oncogenic functions of MYC is unclear. We have solved the crystal structure of OmoMYC and show that it forms a stable homodimer and as such recognizes DNA in the same manner as the MYC/MAX heterodimer. OmoMYC attenuates both MYC-dependent activation and repression by competing with MYC/MAX for binding to chromatin, effectively lowering MYC/MAX occupancy at its cognate binding sites. OmoMYC causes the largest decreases in promoter occupancy and changes in expression on genes that are invaded by oncogenic MYC levels. A signature of OmoMYC-regulated genes defines subgroups with high MYC levels in multiple tumor entities and identifies novel targets for the eradication of MYC-driven tumors.

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Gene Expression Omnibus

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Acknowledgements

We thank Laura Soucek for sharing results before publication, Agnes Elias and Werner Schmitz for help with protein purification, Hermann Schindelin for help with determining the structures of OmoMYC, Christopher Bombeck for help with generating the targeted shRNA library and Jens Siveke (Technical University of Munich) for kindly providing KPCs. The expert technical assistance of Barbara Bauer, André Kutschke, Angela Grün and Renate Metz is gratefully acknowledged. This work was supported by grants from Worldwide Cancer Research and the German Research Foundation via Research Group 2341 to ME, GE, LZ and CK, and a pre-doctoral fellowship from the German National Academic Foundation to LAJ. High-throughput-sequencing data are available at the Gene Expression Omnibus under the accession number GEO: GSE77328s. We thank the European Synchrotron Radiation Facility for beamtime and the staff of ID23-1 for technical support. We thank the Helmholtz Zentrum Berlin for the allocation of beamtime and the staff of BL14.1 for technical support. Atomic coordinates have been deposited in the Protein Data Bank under accession codes 5I4Z (apo structure) and 5I50 (DNA-bound structure).

Author contributions

LAJ, AG, WK, CPA, JK, BvE, SL, CR and Ld'A performed the experiments. SW, CPA and EW analyzed the high-throughput data. AB provided the data before publication. MS provided advice on microscopy. CK, LZ, GE and ME conceived the study and wrote the paper.

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Author notes

  1. L A Jung and A Gebhardt: These two authors contributed equally to the work.

Authors and Affiliations

  1. Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany

    L A Jung, A Gebhardt, C P Ade, B von Eyss, C Redel, E Wolf & M Eilers

  2. Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany

    L A Jung, W Koelmel, J Kuper & C Kisker

  3. Comprehensive Cancer Center, Core Unit Bioinformatics, Biocenter, Würzburg, Germany

    S Walz

  4. Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany

    S Letschert & M Sauer

  5. Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tübingen, Tübingen, Germany

    L d'Artista & L Zender

  6. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, UK

    A Biankin

  7. West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK

    A Biankin

  8. South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, New South Wales, Australia

    A Biankin

  9. Department of Biochemistry, University of Cambridge, Cambridge, UK

    G Evan

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  1. L A Jung
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Correspondence to C Kisker or M Eilers.

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Jung, L., Gebhardt, A., Koelmel, W. et al. OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors. Oncogene 36, 1911–1924 (2017). https://doi.org/10.1038/onc.2016.354

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