Z Gastroenterol 2018; 56(01): E2-E89
DOI: 10.1055/s-0037-1612772
Poster Visit Session IV Tumors, Liver Surgery and Transplantation – Saturday, January 27, 2018, 8:30am – 9:15am, Foyer area West Wing
Georg Thieme Verlag KG Stuttgart · New York

YAP (Yes-Associated Protein) induces PRC2 (Polycomb Repressive Complex 2) proteins to regulate histone methylation

Authors

  • M Knaub

    1   Institute of Pathology, Heidelberg

  • S Thomann

    1   Institute of Pathology, Heidelberg

  • S Weiler

    1   Institute of Pathology, Heidelberg

  • P Schirmacher

    1   Institute of Pathology, Heidelberg

  • K Breuhahn

    1   Institute of Pathology, Heidelberg
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Publikationsdatum:
03. Januar 2018 (online)

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Introduction:

Overexpression of the Hippo pathway-regulated transcriptional co-activator Yes-Associated Protein (YAP) is frequently detected in human hepatocellular carcinoma (HCC) and correlates with poor clinical outcome of cancer patients [1]. So far YAP is associated with the stimulation of single pro-tumorigenic target genes such as FoxM1 and CTGF [2]. However, if YAP also coordinates the expression of functionally related protein families, is unknown.

Results and Methods:

The analysis of expression profiling data derived from human liver cancer cells after siRNA-mediated YAP inhibition revealed that SUZ12 and EZH2, members of the Polycomb Repressive Complex 2 (PRC2), were positively regulated by YAP. Silencing of YAP reduced transcript and protein levels of PRC2 core constituents (e.g. EZH2, SUZ12, EED, RBBP7) in different liver cancer cell lines. Functionally, siRNA mediated reduction of EZH2, the enzymatic subunit of PRC2, reduced the specific trimethylation of histone H3 at K27 (3meK27H3). We also observed reduced 3meK27H3 levels after siRNA-mediated YAP silencing and after administration of the EZH2 inhibitor Tazemetostat. Vice versa, the inducible overexpression of constitutively active YAPS127A in murine hepatocytes showed increased levels of PRC2 components (e.g. EZH1, EZH2, SUZ12, EED).

Expression data derived from 242 HCC patients showed significantly elevated mRNA levels of PRC2 components compared to adjacent non-tumorous tissues. Additionally elevated SUZ12 and EED transcript levels correlated with worse overall survival and early cancer recurrence in these patients [3]. Furthermore, immunohistochemical stains of tissue micro-arrays containing normal liver tissue and HCCs (n = 103) revealed a significant correlation between YAP overexpression and nuclear EZH2 and SUZ12 enrichment (e.g. YAP vs. EZH2; r = 0.4, p < 0.001).

Summary:

Our results suggest that the Hippo pathway effector YAP supports HCC development through epigenetic changes via induction of PRC2. Thus, inhibition of YAP (e.g. by Verteporfin) or perturbation of EZH2 activity (e.g. Tazemetostat) might represent novel therapeutic approaches for the treatment of HCC patients with YAP overexpression or PRC2 activation.

References:

[1] Tschaharganeh, D.F., et al., Gastroenterology, 2013.

[2] Weiler, S.M., et al., Gastroenterology, 2017.

[3] Roessler, S., et al., Cancer Res, 2010.