TY  - GEN
KW  - Hippo; YAP; TAZ; hepatocarcinogenesis; MCM; PRC2; EZH2; Leber; HCC
N2  - Cancer is worldwide the leading cause of death in the 21st century. Liver cancer represents the fourth most common cancer with hepatocellular carcinoma (HCC) being the most frequent primary liver cancer. HCC is the second most common cause of cancer-related deaths with a 5-year survival rate below 12% in the US. These sobering numbers illustrate the need for bio-medical research to identify novel target structures and to develop respective therapeutic strategies. The evolutionarily conserved Hippo signaling pathway is frequently deregulated in human hepatocarcinogenesis. Indeed, overexpression of the transcriptional co-activators yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) is associated with pro-proliferative and anti-apoptotic effects in liver tumor cells. However, among the identified direct YAP/TAZ target genes, no functional groups or protein families have been described, which facilitate the biological properties of YAP and TAZ in HCC cells. Since these groups may represent relevant molecular hubs that mediate the tumor-supporting properties of the Hippo pathway, this study aimed to define YAP/TAZ-regulated protein families, which may represent promising therapeutic target structures. 
Based on comprehensive transcriptome analysis after siRNA-mediated inhibition of YAP and TAZ in HCC cells, the minichromosome maintenance (MCM) protein family, which is crucial for DNA replication, and members of the polycomb repressive complex 2 (PRC2), which inserts epigenetic repression marks (trimethylation of histone H3; H3K27me3), were identified as YAP and/or TAZ target genes. For the MCM family members (MCM2-7), different molecular approaches confirmed the direct transcriptional regulation via YAP/TAZ and the transcription factor TEA domain transcription factor 4 (TEAD4) in independent liver cancer lines. In contrast, the PRC2 components Enhancer Of Zeste 2 (EZH2) and Suppressor Of Zeste 12 Protein Homolog (SUZ12) were predominantly regulated by YAP and TEAD4. Functionally, RNAi-mediated MCM reduction as well as YAP and TAZ perturbations decreased cell proliferation in vitro. Additionally, YAP induces the expression of PRC2 components and their epigenetic mark H3K27me3 in vitro, leading to the repression of target gene transcription. In a YAP-dependent HCC mouse model (inducible expression of constitutively active YAPS127A)) a clear positive association between YAP overexpression and especially abundance of MCM family members confirmed the in vitro results. Statistical correlations between tumor progression, YAP expression and MCM2-7, EZH2, and SUZ12 abundance in primary patient tissues supported the hypothesis that both protein groups are cooperatively induced by YAP and TEAD4 in human HCC. 
Together, these results illustrate that the Hippo pathway contributes to tumor progression via the regulation of protein groups that induce biological functions. The transcriptional regulation of MCM helicase by the Hippo pathway introduces a promising surrogate marker for YAP driven proliferation. Furthermore, YAP induced transcription of PRC2 members illustrates a new possibility of YAP mediated gene silencing and offers a novel approach to understand oncogenic Hippo/YAP feedback loops. Interestingly, both YAP and TAZ are important for the regulation of all MCM family members, while data for PRC2 constituents point to a predominant role of YAP. This differential dependency of target genes might represent a molecular mechanism of how the Hippo pathway regulates specific biological processes, as epigenetic changes and replication. This is of special importance since direct perturbation of the Hippo/YAP/TAZ-axis could also inhibit pro-regenerative properties (e.g. proliferation), which might be of relevance for patients with chronically damaged livers. Thus, targeting these important downstream hubs could represent one strategy to selectively impair YAP and/or TAZ-dependent HCC cell functionality while saving physiological hepatocellular proliferation in regenerative livers, which could maintain residual liver function. Still, further studies are needed to test if MCM proteins and PRC2 are suitable points-of-interference in HCC patients with YAP and/or TAZ activation.
A1  - Knaub, Maria
CY  - Heidelberg
TI  - Molecular downstream mechanisms
of the oncogenic transcriptional regulators YAP/TAZ
in hepatocarcinogenesis
AV  - public
Y1  - 2019///
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/27100/
ID  - heidok27100
ER  -