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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.

Author information

1
Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, Munich, Germany.
2
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
3
Rudolf Boehm Institute of Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, Leipzig, Germany.
4
Gene Center, Department of Chemistry and Pharmacy, Ludwig-Maximilians-University Munich, Munich, Germany.
5
Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-N├╝rnberg, Erlangen, Germany.
6
Interfaculty Institute of Cell Biology, Tuebingen University, Tuebingen, Germany.
7
German Cancer Consortium (DKTK) and DKFZ, Heidelberg, Germany.

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.

PMID:
28114277
DOI:
10.1038/onc.2016.496
[Indexed for MEDLINE]

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