Abstract 1452: DVL1 regulates global transcriptomic changes and associates with the transcription factor ETS1

Abstract Background: Signaling pathways are integral to the regulation of essential biological processes within cells, and their coordinated control across tissues is critical for numerous vital functions. Dysregulation of these pathways can contribute to the development of various diseases, particularly cancer. In the context of Wnt signaling, aberrations in the pathway can induce chromatin modifications that regulate the epigenome, thereby promoting tumorigenesis and metastasis. A key component of this pathway is Dishevelled (DVL), which, although traditionally considered a cytoplasmic protein, has been shown to translocate to the nucleus. However, the nuclear role of DVL remains perplexing, and little is known about what genomic loci it binds, what regulates its binding, and what DNA binding proteins may be novel interacting partners. Key Results: Our study utilizes data from our recent DVL ChIP/RNA-seq analyses, publicly available datasets, and extensive genomic and bioinformatics evaluations to investigate the poorly understood role of nuclear DVL1. Our findings uncover novel mechanisms by which DVL regulates downstream signaling. First, we demonstrate that DVL not only binds to promoters of genes linked to tumorigenesis but also targets numerous genes involved in immune system regulation. Second, we identify an interaction between DVL1 and transcription factors such as ETS1. Notably, our discovery that nuclear DVL1 and ETS1 form a complex and co-localize at specific genomic loci is, to our knowledge, the first report of such an interaction. Third, we show that ETS1 is essential for DVL1 binding to several genes not previously associated with Wnt/DVL signaling. Impact: Our study offers some of the first insights into the novel functions of nuclear DVL, revealing its critical role in regulating ETS1 and a broad range of genes essential for developmental biology, antigen presentation, metabolism, chromatin remodeling, and tumorigenesis. By uncovering these previously uncharacterized functions, our research substantially advances the understanding of DVL’s involvement in aberrant Wnt signaling, providing new perspectives on its potential contributions to disease mechanisms. This work not only enriches the current knowledge of DVL’s multifaceted role but also opens avenues for targeted therapeutic strategies in diseases driven by dysregulated Wnt signaling. Citation Format: Dalia Martinez-Marin, Monica Sharma, Jenna C. van Wunnik, Flavia Sardela de Miranda, Geetha P. Boligala, Ella C. Jull, Grace C. Stroman, Rachel L. Babcock, Kevin Pruitt. DVL1 regulates global transcriptomic changes and associates with the transcription factor ETS1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1452.