Abstract B03: Role of DVL in transcription and epigenetic regulation of immunoregulatory genes in triple-negative breast cancer

Abstract

Abstract Introduction: Dishevelled (DVL) is a crucial component of Wnt-signaling and is vital for other physiological processes. There are three DVL paralogs, yet the paralog-specific functions and their regulation remain poorly understood. One of the goals of our study is to define how DVL1 mediates Wnt-signaling specificity and how it regulates the transcription of genes that impact tumor-intrinsic modulation of immune cell recruitment. While several studies suggest that DVL proteins could serve as critical mediators of malignancy for breast cancer and other cancer types, the mechanism by which DVL contributes to breast tumor progression and tumor immunology remain unanswered. This study utilizes data from our recent DVL ChIP-seq and RNA-seq analyses, publicly available data, genomic analyses, and other bioinformatics tools to investigate novel mechanisms of how DVL coordinates downstream signaling. Our study seeks to define the elusive function of nuclear DVL with respect to epigenetic and transcriptional regulation in models of triple-negative breast cancer. Methods: DVL ChIP-sequenced reads were aligned against GRCh38.p14, and peaks visualized using an integrative genomic viewer. RNA-seq FASTQ files were trimmed and aligned to GRCh38.p14; read counts were analyzed with edgeR and resulting differentially expressed genes with R and Cytoscape. To determine possible DVL binding partners, transcription factor and protein-protein interaction database mining and subsequent co-immunoprecipitation were performed. Results: Although much remains unknown regarding DVL function and regulation, the discovery of its translocation to the nucleus, binding to novel genomic loci, and regulation of novel gene expression raised new functionality. Our analysis shows DVL binding to core-promoter elements in essential immunological regulatory genes such as STAT1, IFN-y, HLA (-A, B, C, Ds, E, F), and interleukins. Data mining and co-immunoprecipitation analysis have identified several possible nuclear DVL binding partners, including candidate transcription factors that partner with DVL genes to regulate immune cell responses in the tumor microenvironment. DVL KO and WT transcriptional regulation analysis also identified several differentially expressed immunological genes. Summary: We have not only identified DVL binding to the promoter of genes involved in tumorigenesis and immune function but also identified possible DVL binding partners that aid in the regulation of these genes. These findings and future in silico and in vivo approaches will further define a novel DVL regulatory role of tumor and immune signaling in triple-negative breast cancer. Citation Format: Dalia Martinez-Marin, Jenna C van Wunnik, Monica Sharma, Kevin Pruitt. Role of DVL in transcription and epigenetic regulation of immunoregulatory genes in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B03.