Abstract 1707: YAP-driven epigenetic reprogramming in head and neck cancer

Abstract

Abstract The ability to measure tumor evolution is difficult due to a lack of model systems able to capture tumor initiation, development, and invasion. We have developed a Dox-inducible spatiotemporally controlled HPV- and YAP-driven model of head and neck squamous cell carcinoma (HNSCC) with a well-defined cancer stem cell population. In order to better understand the epigenetic reprogramming associated with tumorigenesis we have systematically characterized the chromatin accessibility, histone landscape and YAP binding sites in this model. Cell lines were generated from tongue epithelia of normal and Dox-induced tumor-containing mice. Gene expression was measured using RNA-seq and chromatin accessibility was measured using ATAC-seq. CUT&Tag for H3K27me3, H3K27ac, and YAP was used to measure epigenetic reprogramming and YAP-DNA interactions. Differential gene expression shows that genes involved in hormone signaling, glutathione-related metabolism, fatty acid metabolism and p53 signaling were highly enriched in the normal tongue suggesting a change in metabolism upon tumorigenesis.Differential ATAC-seq peaks with higher binding levels in the normal tongue showed enrichment for p53 motifs as well as homebox motifs including Otx2, GSC and CRX suggesting p53 signaling is lost upon carcinogenesis and lineage determination is altered. Motifs for TEAD, AP-1, and KLF5 were enriched in the tumor-specific ATAC-seq peaks showing that YAP is involved in chromatin accessibility changes. CUT&Tag for YAP shows clear YAP binding near canonical YAP target genes including Axl, Ccn1, Ccn2 and Birc3. YAP peaks with higher binding in the normal tongue cell line were enriched for RUNX2 and p63 motifs and peaks higher in the tumor contained KLF5 motifs showing YAP is directly involved in the reprogramming of lineage determination. Multi-omics integration shows YAP-driven chromatin remodeling is associated with differential expression of genes involved in keratin production, EGFR and ER signaling. Direct epigenetic characterization of YAP involvement in tumor initiation is key to understanding the mechanisms of tumorigenesis in head and neck cancer. This work shows that YAP directly binds and affects the expression of genes involved in lineage determination and growth factor signaling to induce cancer progression and generate a cancer stem cell population. Citation Format: Adam Officer, Farhoud Faraji, Sydney Ramirez, Alon Goren, Pablo Tamayo, J. Silvio Gutkind. YAP-driven epigenetic reprogramming in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1707.