Depletion of the transcriptional coactivators megakaryoblastic leukaemia 1 and 2 abolishes hepatocellular carcinoma xenograft growth by inducing oncogene‐induced senescence

EMBO Molecular Medicine

Veronika Hampl⁶  Claudia Martin⁶  Achim Aigner²  Sabrina Hoebel²  Stephan Singer³  Natalie Frank⁶  Antonio Sarikas⁴  Oliver Ebert¹  Ron Prywes⁵  Thomas Gudermann⁶ 

[1] Department of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany;Rudolf Boehm Institute of Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, Germany;Institute of Pathology, University Hospital Heidelberg, Germany;Institute of Pharmacology and Toxicology, Technical University of Munich, Germany;Department of Biological Sciences, Columbia University, New York, USA;Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany

关键词: DLC1;    MKL1;    MKL2;    MRTF;    senescence;   

DOI  :  10.1002/emmm.201202406

来源: Wiley

【 摘 要 】

Abstract

Megakaryoblastic leukaemia 1 and 2 (MKL1/2) are coactivators of the transcription factor serum response factor (SRF). Here, we provide evidence that depletion of MKL1 and 2 abolishes hepatocellular carcinoma (HCC) xenograft growth. Loss of the tumour suppressor deleted in liver cancer 1 (DLC1) and the subsequent activation of RhoA were prerequisites for MKL1/2 knockdown-mediated growth arrest. We identified oncogene-induced senescence as the molecular mechanism underlying the anti-proliferative effect of MKL1/2 knockdown. MKL1/2 depletion resulted in Ras activation, elevated p16 expression and hypophosphorylation of the retinoblastoma (Rb) protein in DLC1-deficient HCC cells. Interestingly, reconstitution of HuH7 HCC cells with DLC1 also induced senescence. Evaluation of the therapeutic efficacy of MKL1/2 knockdown in vivo revealed that systemic treatment of nude mice bearing HuH7 tumour xenografts with MKL1/2 siRNAs complexed with polyethylenimine (PEI) completely abolished tumour growth. The regression of the xenografts was associated with senescence. Importantly, PEI-complexed MKL1 siRNA alone was sufficient for complete abrogation of HCC xenograft growth. Thus, MKL1/2 represent promising novel therapeutic targets for the treatment of HCCs characterized by DLC1 loss.

【 授权许可】

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Copyright © 2013 EMBO Molecular Medicine

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