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Oncogene. 2017 Jun 15;36(24):3464-3476. doi: 10.1038/onc.2016.496. Epub 2017 Jan 23.

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

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Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, Munich, Germany.
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Rudolf Boehm Institute of Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, Leipzig, Germany.
Gene Center, Department of Chemistry and Pharmacy, Ludwig-Maximilians-University Munich, Munich, Germany.
Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-N├╝rnberg, Erlangen, Germany.
Interfaculty Institute of Cell Biology, Tuebingen University, Tuebingen, Germany.
German Cancer Consortium (DKTK) and DKFZ, Heidelberg, Germany.


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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