Abstract 3350: Delineating the p63-driven oncogenic network and epigenomic signature in salivary gland tumors

Abstract

Abstract Head and Neck Squamous Cell Carcinomas (HNSCCs) constitute a diverse group of cancers that share their origin from the epithelium-rich upper aero-digestive tract. These cancers include oro-pharyngeal, laryngeal and salivary gland carcinomas, each endowed with a wide-ranging spectrum of distinct pathological subtypes and defined molecular and genetic determinants. Salivary gland neoplasms in particular, epitomizes this diversity and remain relatively less studied and ill-understood. To address this knowledge void and to get a better understanding of the molecular etiology of salivary gland tumors, we have focused our studies on p63, an oncogenic master transcription factor that is overexpressed in HNSCC, including salivary glands tumors. By utilizing the A253 cells, a representative cell-line isolated from a human submandibular carcinoma, here we have performed a comprehensive transcriptomic and epigenomic characterization of the p63-driven and global transcriptional circuitry. Our ChIP-seq based studies have identified the complete repertoire of the genome-wide enhancer regions in the A253 cells and importantly have unearthed a cohort of H3K27Ac-enriched super enhancers specifically enriched in p63 binding, highlighting the important cell-lineage directing role for p63 in these cells. Furthermore, RNA-seq based examination of the underlying changes in gene expression following the loss of p63 have also unearthed key mediators of the p63-cistrome that are likely to impinge upon cellular and oncogenic functions. In parallel, we have leveraged these newly developed resources with complementary genomic information from TCGA, and specifically HNSCC datasets, to examine the relevancy of our findings in the tumor context. Taken together, our multipronged approach has revealed several novel p63 target-enriched gene regulatory networks that span the breadth of core and emerging hallmarks of cancer. In particular, we have unveiled a p63-dependent network of several E26 transformation-specific (ETS) family of transcription factors which act downstream of p63 and act in concert to generate pro-oncogenic and anti-tumor suppressive forces. Interestingly, our studies also reveal that p63 and its ETS co-partners serve as an upstream molecular switch favoring the repression of TGF-β and concurrent activation of BMP signaling pathways, which may contribute favorably to proliferative and survival circuitry in HNSCC. These observations and other broader genomic insights into cancer cell specific metabolism and transcriptional addiction that has emerged from our studies can be further exploited for the development of diagnostics and/or therapeutics against salivary gland cancers and more broadly HNSCCs. Citation Format: Akinsola Oyelakin, Christian Gluck, Satrajit Sinha, Rose-Anne Romano. Delineating the p63-driven oncogenic network and epigenomic signature in salivary gland tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3350.