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

Hermanns, C.; Hampl, V.; Holzer, K.; Aigner, A.; Penkava, J.; Frank, N.; Martin, D. E.; Maier, K. C.; Waldburger, N.; Rössler, S.; Goppelt-Struebe, M.; Akrap, I.; Thavamani, A.; Singer, S.; Nordheim, A.; Gudermann, T. and Mühlich, S. (2017): The novel MKL target gene myoferlin modulates expansion and senescence of hepatocellular carcinoma. In: Oncogene, Vol. 36, No. 24: pp. 3464-3476

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.

• Item Type: Journal article
• Faculties: Chemistry and Pharmacy > Department of Biochemistry; Medicine
• Subjects: 500 Science > 540 Chemistry; 600 Technology > 610 Medicine and health
• ISSN: 0950-9232
• Language: English