Abstract
Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations in the canonical Hippo pathway, but very frequent genetic alterations in the FAT family of atypical cadherins. By focusing on head and neck squamous cell carcinoma (HNSCC), which displays frequent FAT1 alterations (29.8%), we provide evidence that FAT1 functional loss results in YAP1 activation. Mechanistically, we found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. We also show that unrestrained YAP1 acts as an oncogenic driver in HNSCC, and that targeting YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes.
Highlights
Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood
As an approach to explore the molecular mechanisms resulting in tumor-associated YAP1 activation, we investigated the presence of genomic alterations in all human orthologs of Drosophila Hippo pathway components in a large panel of 38 distinct cancers sequenced by The Cancer Gene Atlas consortium (TCGA, 14729 neoplastic lesions, Supplementary Fig. 1a)[9]
We found many known or candidate YAP1 and FAT regulators or associated transcription factors to be significantly amplified (MST2/STK3, TEAD4, TAZ/WWTR1, and YAP1) or deleted (DCHS2, FAT1, FAT4, LATS1/2, TEAD1, TEAD2, and KIBRA/ WWC1) (Supplementary Fig. 1b)
Summary
Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. We found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. In light of the crucial role of MST1/2 and LATS in YAP1 regulation, there are surprisingly few recurrent alterations in these core Hippo pathway components in cancer[1]. There are only a few examples of known YAP1 regulating genes altered in cancer, which include LATS2 and an upstream Hippo pathway component, NF2, in malignant mesothelioma (35% and 50%, respectively)[7], and inherited NF2 mutations and microdeletions in neurofibromatosis type 28, overall accounting for a small fraction of human malignancies displaying YAP1 hyperactivity. We show that targeting unrestrained YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes
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