Focal adhesion kinase depletion reduces human hepatocellular carcinoma growth by repressing enhancer of zeste homolog 2

Daniela Gnani, Ilaria Romito, Simona Artuso, Marco Chierici, Cristiano De Stefanis, Nadia Panera, Annalisa Crudele, Sara Ceccarelli, Elena Carcarino, Valentina D'Oria, Manuela Porru, Ezio Giorda, Karin Ferrari, Luca Miele, Erica Villa, Clara Balsano, Diego Pasini, Cesare Furlanello, Franco Locatelli, Valerio NobiliRossella Rota, Carlo Leonetti, Anna Alisi

Risultato della ricerca: Contributo in rivistaArticolo in rivista

26 Citazioni (Scopus)

Abstract

Hepatocellular carcinoma (HCC) is the most common type of liver cancer in humans. The focal adhesion tyrosine kinase (FAK) is often over-expressed in human HCC and FAK inhibition may reduce HCC cell invasiveness. However, the anti-oncogenic effect of FAK knockdown in HCC cells remains to be clarified. We found that FAK depletion in HCC cells reduced in vitro and in vivo tumorigenicity, by inducing G2/M arrest and apoptosis, decreasing anchorage-independent growth, and modulating the expression of several cancer-related genes. Among these genes, we showed that FAK silencing decreased transcription and nuclear localization of enhancer of zeste homolog 2 (EZH2) and its tri-methylation activity on lysine 27 of histone H3 (H3K27me3). Accordingly, FAK, EZH2 and H3K27me3 were concomitantly upregulated in human HCCs compared to non-tumor livers. In vitro experiments demonstrated that FAK affected EZH2 expression and function by modulating, at least in part, p53 and E2F2/3 transcriptional activity. Moreover, FAK silencing downregulated both EZH2 binding and histone H3K27me3 levels at the promoter of its target gene NOTCH2. Finally, we found that pharmacological inhibition of FAK activity resembled these effects although milder. In summary, we demonstrate that FAK depletion reduces HCC cell growth by affecting cancer-promoting genes including the pro-oncogene EZH2. Furthermore, we unveil a novel unprecedented FAK/EZH2 crosstalk in HCC cells, thus identifying a targetable network paving the way for new anticancer therapies.
Lingua originaleEnglish
pagine (da-a)889-902
Numero di pagine14
RivistaCell Death and Differentiation
Volume24
DOI
Stato di pubblicazionePubblicato - 2017

Keywords

  • Aminopyridines
  • Animals
  • Apoptosis
  • Carcinoma, Hepatocellular
  • Cell Biology
  • Cell Line, Tumor
  • Cell Proliferation
  • E2F2 Transcription Factor
  • E2F3 Transcription Factor
  • Enhancer of Zeste Homolog 2 Protein
  • Focal Adhesion Kinase 1
  • G2 Phase Cell Cycle Checkpoints
  • Gene Expression Regulation, Neoplastic
  • Hep G2 Cells
  • Histones
  • Humans
  • Liver Neoplasms
  • Male
  • Mice
  • Mice, Nude
  • Molecular Biology
  • Neoplasm Transplantation
  • Promoter Regions, Genetic
  • RNA, Small Interfering
  • Receptor, Notch2
  • Signal Transduction
  • Tumor Suppressor Protein p53

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