Depletion of the transcriptional coactivators megakaryoblastic leukaemia 1 and 2 abolishes hepatocellular carcinoma xenograft growth by inducing oncogene-induced senescence
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 t...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
29 July 2013
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| In: |
EMBO molecular medicine
Year: 2013, Volume: 5, Issue: 9, Pages: 1367-1382 |
| ISSN: | 1757-4684 |
| DOI: | 10.1002/emmm.201202406 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1002/emmm.201202406 Verlag, lizenzpflichtig, Volltext: https://www.embopress.org/doi/full/10.1002/emmm.201202406 
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| Author Notes: | Veronika Hampl, Claudia Martin, Achim Aigner, Sabrina Hoebel, Stephan Singer, Natalie Frank, Antonio Sarikas, Oliver Ebert, Ron Prywes, Thomas Gudermann, Susanne Muehlich |
MARC
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| 520 | |a 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. | ||
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