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The novel MKL target gene myoferlin modulates expansion and senescence of hepatocellular carcinoma

Oncogene volume 36, pages 3464–3476 (2017)Cite this article

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Abstract

Megakaryoblastic Leukemia 1 and 2 (MKL1/2) are transcriptional coactivators of Serum Response Factor (SRF) with an essential role for hepatocellular carcinoma (HCC) growth and oncogene-induced senescence. In this report, we identified myoferlin as a novel MKL/SRF target gene by gene expression profiling and verification in vivo in HCC xenografts. Myoferlin was overexpressed in human and murine HCCs triggered by conditional expression of constitutively active SRF-VP16 protein in hepatocytes. Furthermore, myoferlin was required for HCC cell invasion, proliferation and anchorage-independent cell growth. We provide evidence that myoferlin is a crucial gene target of MKL1/2 mediating its effect on oncogene-induced senescence by modulating the activation state of the EGFR and downstream MAPK and p16-/Rb pathways. Depletion of myoferlin in tumour cells from SRF-VP16-derived murine HCCs induced a senescence phenotype. These findings identify MKL1/2 and myoferlin as novel therapeutic targets to treat human HCC by a senescence-inducing strategy.

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Acknowledgements

We thank Elizabeth McNally and Alexis Demonbreun for the myoferlin promoter construct, and Veronika Geissler and Esther Herpel from the NCT tissue bank in Heidelberg for their support. Funded by grant MU 2737/2-2 of the Deutsche Forschungsgemeinschaft. Alfred Nordheim was supported by the Deutsche Krebshilfe (grant 109886) and DKTK (German Cancer Consortium). Stephan Singer was supported by DFG (grant Si 1487/3-1), and by an HRCMM (Heidelberg Research Center for Molecular Medicine) Career Development Fellowship.

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Author notes

  1. A Nordheim and T Gudermann: Shared authorship.

Authors and Affiliations

  1. Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, Munich, Germany

    C Hermanns, V Hampl, J Penkava, N Frank, T Gudermann & S Muehlich

  2. Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

    K Holzer, N Waldburger, S Roessler & S Singer

  3. Rudolf Boehm Institute of Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, Leipzig, Germany

    A Aigner

  4. Department of Chemistry and Pharmacy, Gene Center, Ludwig-Maximilians-University Munich, Munich, Germany

    D E Martin & K C Maier

  5. Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany

    M Goppelt-Struebe

  6. Interfaculty Institute of Cell Biology, Tuebingen University, Tuebingen, Germany

    I Akrap, A Thavamani & A Nordheim

  7. German Cancer Consortium (DKTK) and DKFZ, Heidelberg, Germany

    A Nordheim

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Correspondence to S Muehlich.

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Hermanns, C., Hampl, V., Holzer, K. et al. The novel MKL target gene myoferlin modulates expansion and senescence of hepatocellular carcinoma. Oncogene 36, 3464–3476 (2017). https://doi.org/10.1038/onc.2016.496

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