title: The novel MKL target gene myoferlin modulates expansion and senescence of hepatocellular carcinoma.
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.
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Hermanns
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Hampl
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Holzer
authors.affiliation: Rudolf Boehm Institute of Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, Leipzig, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Aigner
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Penkava
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Frank
authors.affiliation: Gene Center, Department of Chemistry and Pharmacy, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: D E
authors.initials: DE
authors.lastname: Martin
authors.affiliation: Gene Center, Department of Chemistry and Pharmacy, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: K C
authors.initials: KC
authors.lastname: Maier
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Waldburger
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: S
authors.identifier: 0000-0002-5333-5942
authors.initials: S
authors.lastname: Roessler
authors.affiliation: Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Goppelt-Struebe
authors.affiliation: Interfaculty Institute of Cell Biology, Tuebingen University, Tuebingen, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Akrap
authors.affiliation: Interfaculty Institute of Cell Biology, Tuebingen University, Tuebingen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Thavamani
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Singer
authors.affiliation: Interfaculty Institute of Cell Biology, Tuebingen University, Tuebingen, Germany.|German Cancer Consortium (DKTK) and DKFZ, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Nordheim
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Gudermann
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Muehlich
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D026362:Serum Response Factor / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; C431575:MRTFA protein, human; C478036:MRTFB protein, human; C415584:MYOF protein, human; D008565:Membrane Proteins; D009124:Muscle Proteins; C476858:SRF protein, human; D026362:Serum Response Factor; D015534:Trans-Activators; D014157:Transcription Factors