Abstract Melanoma is the most lethal of all skin cancers due to the high degree of metastasis. Our group and others find the transcriptional co-factors and paralogs YAP and TAZ active in melanoma progression, invasion, and metastasis. Although YAP and TAZ are often thought of as redundant, we discovered differential functions in melanoma cells: both factors effect cell growth, while YAP was the dominant paralog driving migration, focal adhesion numbers, and invasion. While YAP and TAZ do not directly bind to DNA, they modulate gene expression by cooperating with transcription factors. While some of these factors interact with both YAP and TAZ, there are likely other transcriptional regulators with higher affinity for either YAP or TAZ. Further supporting that YAP and TAZ are not interchangeable, we found overlapping but distinct YAP and TAZ transcriptomes, and identified a YAP-specific gene, ARPC5, which promoted migration through changes to the cytoskeleton and focal adhesions. The question remains on what the redundant and unique roles of YAP and TAZ are, and what is the mechanism for divergent roles in terms of cofactors, downstream target genes, and functional consequences. The hypothesis guiding this proposal is that YAP and TAZ have similar and divergent transcriptional downstream targets that regulate overlapping and unique cellular processes. To support this hypothesis, we performed non- biased transcriptional and enhancer screens for YAP and TAZ locations on the genome, and revealed that YAP and TAZ have shared and distinct cistromic signatures. Indeed, we discovered significant similarities and differences in both cellular expression signatures as well as cistromic patterns. Our general strategy is to examine identified genes and enhancer regions to reveal YAP and/or TAZ transcriptional partners and downstream gene targets. Our research plan will utilize bioinformatic prediction and applied functional assays to reveal molecular pathways and downstream consequences of YAP and/or TAZ function in melanoma. The goal of this proposal is to make impactful discoveries on YAP and TAZ downstream genetic targets and to identify their function in terms of tumorigenic processes. Our work is significant and impactful since these studies will uncover unique transcriptional pathways where YAP and TAZ function separately, redundantly, or together, and may reveal new potential molecular weak points in tumor progression that can be targeted by therapeutics. This proposal is innovative since the YAP/TAZ transcriptional roles in melanoma, as well as specific genetic targets and functional consequences, are mostly unknown.

Narrative The goal of this proposal is to make impactful discoveries on the overlapping and unique functions of YAP and TAZ proteins on regulating gene expression in melanoma. YAP and TAZ are implicated in driving melanoma aggressiveness and metastasis, which are the predominant causes of patient morbidity and mortality. We will establish a method for identifying cancer-driving genes that are regulated by YAP and TAZ, as well as regions in the DNA that modulate the function of these genes.