Research ArticleInflammation

The Hippo pathway effector TAZ induces TEAD-dependent liver inflammation and tumors

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Sci. Signal.  11 Sep 2018:
Vol. 11, Issue 547, eaaj1757
DOI: 10.1126/scisignal.aaj1757

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TAZ drives inflammation

Key effectors of the Hippo pathway, YAP and TAZ, are overexpressed in various cancers. Loss of upstream kinases that inhibit the activity of these transcriptional coactivators promotes inflammation. In patient-derived xenografts and TCGA data sets, Hagenbeek et al. found that only TAZ expression correlated strongly with inflammatory cytokine transcript abundance. Expression of hyperactivated TAZ, but not YAP, in the livers of mice augmented transcription factor TEAD-mediated systemic inflammation and tissue infiltration by myeloid cells. RNA-seq analysis identified distinct gene signatures in tumor cells driven by activated YAP or TAZ, suggesting that these Hippo pathway effectors have nonredundant functions.

Abstract

The Hippo signaling pathway regulates organ size and plays critical roles in maintaining tissue growth, homeostasis, and regeneration. Dysregulated in a wide spectrum of cancers, in mammals, this pathway is regulated by two key effectors, YAP and TAZ, that may functionally overlap. We found that TAZ promoted liver inflammation and tumor development. The expression of TAZ, but not YAP, in human liver tumors positively correlated with the expression of proinflammatory cytokines. Hyperactivated TAZ induced substantial myeloid cell infiltration into the liver and the secretion of proinflammatory cytokines through a TEAD-dependent mechanism. Furthermore, tumors with hyperactivated YAP and TAZ had distinct transcriptional signatures, which included the increased expression of inflammatory cytokines in TAZ-driven tumors. Our study elucidated a previously uncharacterized link between TAZ activity and inflammatory responses that influence tumor development in the liver.

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