title: Depletion of the transcriptional coactivators megakaryoblastic leukaemia 1 and 2 abolishes hepatocellular carcinoma xenograft growth by inducing oncogene-induced senescence.
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.
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Hampl
authors.forename: Claudia
authors.initials: C
authors.lastname: Martin
authors.forename: Achim
authors.initials: A
authors.lastname: Aigner
authors.forename: Sabrina
authors.initials: S
authors.lastname: Hoebel
authors.forename: Stephan
authors.initials: S
authors.lastname: Singer
authors.forename: Natalie
authors.initials: N
authors.lastname: Frank
authors.forename: Antonio
authors.initials: A
authors.lastname: Sarikas
authors.forename: Oliver
authors.initials: O
authors.lastname: Ebert
authors.forename: Ron
authors.initials: R
authors.lastname: Prywes
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.forename: Susanne
authors.initials: S
authors.lastname: Muehlich
mesh_terms: D000375:Aging; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000503:physiopathology*; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015513:Oncogene Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C431575:MRTFA protein, human; C478036:MRTFB protein, human; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D014157:Transcription Factors
keywords: DLC1; MKL1; MKL2; MRTF; senescence