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

Research output: Contribution to journalArticle

16 Citations (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.

Original languageEnglish
Pages (from-to)889-902
Number of pages14
JournalCell Death and Differentiation
Volume24
Issue number5
DOIs
Publication statusPublished - May 1 2017

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Focal Adhesion Protein-Tyrosine Kinases
Protein-Tyrosine Kinases
Hepatocellular Carcinoma
Growth
Neoplasm Genes
Histones
Enhancer of Zeste Homolog 2 Protein
Liver Neoplasms
Oncogenes
Methylation
Genes
Lysine
Down-Regulation
Pharmacology

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Focal adhesion kinase depletion reduces human hepatocellular carcinoma growth by repressing enhancer of zeste homolog 2. / Gnani, Daniela; Romito, Ilaria; Artuso, Simona; Chierici, Marco; De Stefanis, Cristiano; Panera, Nadia; Crudele, Annalisa; Ceccarelli, Sara; Carcarino, Elena; D'Oria, Valentina; Porru, Manuela; Giorda, Ezio; Ferrari, Karin; Miele, Luca; Villa, Erica; Balsano, Clara; Pasini, Diego; Furlanello, Cesare; Locatelli, Franco; Nobili, Valerio; Rota, Rossella; Leonetti, Carlo; Alisi, Anna.

In: Cell Death and Differentiation, Vol. 24, No. 5, 01.05.2017, p. 889-902.

Research output: Contribution to journalArticle

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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.",
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T1 - Focal adhesion kinase depletion reduces human hepatocellular carcinoma growth by repressing enhancer of zeste homolog 2

AU - Gnani, Daniela

AU - Romito, Ilaria

AU - Artuso, Simona

AU - Chierici, Marco

AU - De Stefanis, Cristiano

AU - Panera, Nadia

AU - Crudele, Annalisa

AU - Ceccarelli, Sara

AU - Carcarino, Elena

AU - D'Oria, Valentina

AU - Porru, Manuela

AU - Giorda, Ezio

AU - Ferrari, Karin

AU - Miele, Luca

AU - Villa, Erica

AU - Balsano, Clara

AU - Pasini, Diego

AU - Furlanello, Cesare

AU - Locatelli, Franco

AU - Nobili, Valerio

AU - Rota, Rossella

AU - Leonetti, Carlo

AU - Alisi, Anna

PY - 2017/5/1

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N2 - 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.

AB - 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.

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