Title |
Focal adhesion kinase depletion reduces human hepatocellular carcinoma growth by repressing enhancer of zeste homolog 2
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Published in |
Cell Death & Differentiation, March 2017
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DOI | 10.1038/cdd.2017.34 |
Pubmed ID | |
Authors |
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 Nobili, Rossella Rota, Carlo Leonetti, Anna Alisi |
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.Cell Death and Differentiation advance online publication, 24 March 2017; doi:10.1038/cdd.2017.34. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Unknown | 3 | 100% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 2 | 67% |
Science communicators (journalists, bloggers, editors) | 1 | 33% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 43 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 7 | 16% |
Researcher | 7 | 16% |
Student > Bachelor | 6 | 14% |
Student > Doctoral Student | 3 | 7% |
Professor > Associate Professor | 2 | 5% |
Other | 6 | 14% |
Unknown | 12 | 28% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 12 | 28% |
Biochemistry, Genetics and Molecular Biology | 10 | 23% |
Agricultural and Biological Sciences | 3 | 7% |
Unspecified | 1 | 2% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 2% |
Other | 3 | 7% |
Unknown | 13 | 30% |