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

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 profi...

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Bibliographic Details
Published in:Oncogene 2017-06, Vol.36 (24), p.3464-3476
Main Authors: Hermanns, C, Hampl, V, Holzer, K, Aigner, A, Penkava, J, Frank, N, Martin, D E, Maier, K C, Waldburger, N, Roessler, S, Goppelt-Struebe, M, Akrap, I, Thavamani, A, Singer, S, Nordheim, A, Gudermann, T, Muehlich, S
Format: Article
Language:English
Subjects:
Animals
Calcium-Binding Proteins - genetics
Calcium-Binding Proteins - metabolism
Cancer genetics
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Cell Line, Tumor
Cell Proliferation
Development and progression
Epidermal growth factor receptors
Gene expression
Gene Expression Profiling - methods
Gene Expression Regulation, Neoplastic
Hepatocellular carcinoma
Hepatocytes
Humans
Leukemia
Liver cancer
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
MAP kinase
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Muscle Proteins - genetics
Muscle Proteins - metabolism
Neoplasm Invasiveness
Neoplasm Transplantation
NIH 3T3 Cells
Phenotypes
Retinoblastoma protein
Senescence
Serum response factor
Serum Response Factor - metabolism
Therapeutic targets
Trans-Activators - metabolism
Transcription
Transcription Factors - metabolism
Tumors
VP16 protein
Xenografts
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Summary: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.
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2016.496