Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional "omic" data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era.

Transcription factors (TFs) are proteins that bind to specific DNA sequences, thereby playing crucial roles in gene-expression regulation through controlling the transcription of genetic information from DNA to RNA. Transcription cofactors and chromatin remodeling factors are also essential in the gene transcriptional regulation. Identifying and annotating all the TFs are primary and crucial steps for illustrating their functions and understanding the transcriptional regulation. In this study, based on manual literature reviews, we collected and curated 72 TF families for animals, which is currently the most complete list of TF families in animals. Then, we systematically characterized all the TFs in 50 animal species and constructed a comprehensive animal TF database, AnimalTFDB. To better serve the community, we provided detailed annotations for each TF, including basic information, gene structure, functional domain, 3D structure hit, Gene Ontology, pathway, protein–protein interaction, paralogs, orthologs, potential TF-binding sites and targets. In addition, we collected and annotated transcription cofactors and chromatin remodeling factors. AnimalTFDB has a user-friendly web interface with multiple browse and search functions, as well as data downloading. It is freely available at http://www.bioguo.org/AnimalTFDB/.

RNA editing, a widespread post-transcriptional mechanism, has emerged as a new player in cancer biology. Recent studies have reported key roles for individual miRNA editing events, but a comprehensive picture of miRNA editing in human cancers remains largely unexplored. Here, we systematically characterized the miRNA editing profiles of 8595 samples across 20 cancer types from miRNA sequencing data of The Cancer Genome Atlas and identified 19 adenosine-to-inosine (A-to-I) RNA editing hotspots. We independently validated 15 of them by perturbation experiments in several cancer cell lines. These miRNA editing events show extensive correlations with key clinical variables (e.g., tumor subtype, disease stage, and patient survival time) and other molecular drivers. Focusing on the RNA editing hotspot in miR-200b, a key tumor metastasis suppressor, we found that the miR-200b editing level correlates with patient prognosis opposite to the pattern observed for the wild-type miR-200b expression. We further experimentally showed that, in contrast to wild-type miRNA, the edited miR-200b can promote cell invasion and migration through its impaired ability to inhibit ZEB1/ZEB2 and acquired concomitant ability to repress new targets, including LIFR, a well-characterized metastasis suppressor. Our study highlights the importance of miRNA editing in gene regulation and suggests its potential as a biomarker for cancer prognosis and therapy.