The TAZ target gene ITGAV regulates invasion and positively feedbacks on YAP and TAZ in liver cancer cells

The Hippo signaling pathway is an important regulator of cell proliferation and organ growth. Its effector proteins yes-associated protein (YAP) and WW Domain Containing Transcription Regulator 1 (WWTR1; TAZ) have been described as potent oncogenes in various cancer entities, promoting tumor initiation and progression. In hepatocellular carcinoma (HCC), YAP activation is linked to tumor onset and poor patient prognosis. However, if and how YAP and TAZ contribute to liver tumorigenesis via common and exclusive molecular mechanisms is poorly understood.

Using RNAinterference, we illustrated that YAP and TAZ individually support HCC cell viability and migration, indicating similar molecular functions of YAP and TAZ. However, additive effects of YAP and TAZ on cell invasiveness were observed, suggesting that both factors may facilitate effects via partially independent mechanisms. To characterize responsible downstream target genes, we performed comprehensive expression profiling, which revealed partly overlapping YAP/TAZ target genes as well as exclusively regulated genes. Focusing on genes important for cell mobility, we identified Integrin-αV (ITGAV) as a novel TAZ-specific target gene. Using transcriptome data from HCC patients we showed that ITGAV is overexpressed in HCC tissues and linked with poor clinical outcome. Indeed, ITGAV expression correlated with TAZ expression and YAP/TAZ target genes in human HCC tissues. ITGAV contributed to tumor cell migration and invasion possibly by altering actin stress fiber assembly. As YAP and TAZ are described mechano-transducers, we showed that perturbation of ITGAV by using either a genetic approach or the specific ITGAV inhibitor cilengitide not only led to a reduction of actin stress fiber formation but also to diminished YAP/TAZ protein levels in the nucleus.

These data describe a novel downstream mechanism of the Hippo pathway in HCC cells, which is regulated by TAZ and ITGAV and that feedbacks on YAP/TAZ activity via dynamic cytoskeletal processes. This mechanism may represent a therapeutic target structure since it contributes to signal amplification of oncogenic YAP/TAZ signaling in hepatocarcinogenesis.