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 language | English |
|---|---|
| Pages (from-to) | 889-902 |
| Number of pages | 14 |
| Journal | Cell Death and Differentiation |
| Volume | 24 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 1 2017 |
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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 journal › Article
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TY - JOUR
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
Y1 - 2017/5/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85016227514&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85016227514&partnerID=8YFLogxK
U2 - 10.1038/cdd.2017.34
DO - 10.1038/cdd.2017.34
M3 - Article
C2 - 28338656
AN - SCOPUS:85016227514
VL - 24
SP - 889
EP - 902
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
IS - 5
ER -