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.
Highlights
Megakaryoblastic leukaemia 1 and 2 (MKL1/2) are coactivators of the transcription factor serum response factor (SRF)
Depletion of MKL1/2 provokes proliferation arrest in hepatocellular carcinoma cells with deleted in liver cancer 1 (DLC1) loss We recently reported that MKL1/2 knockdown in HuH7 hepatocellular cancer cells impairs cell proliferation (Muehlich et al, 2012)
A major breakthrough towards a targeted therapy of hepatocellular carcinoma (HCC) was the discovery that the tumour suppressor DLC1 is deleted in 50% of liver cancers (Xue et al, 2008; Yuan et al, 1998)
Summary
Megakaryoblastic leukaemia 1 and 2 (MKL1/2) are coactivators of the transcription factor serum response factor (SRF). 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. In hepatocellular‐ and mammary‐carcinoma cells, constitutive nuclear localization of MKL1/2 and activation of several tumour‐relevant SRF target genes are observed (Muehlich et al, 2012). This is reminiscent of the MKL1 fusion protein with the RBM15 gene (a.k.a. OTT), which is a translocation found in acute megakaryoblastic leukaemia. We report that therapeutic knockdown of MKL1/ 2 abolishes tumour growth of DLC1‐deficient hepatocellular carcinoma (HCC) xenografts by inducing oncogene‐induced senescence
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