SOX2 is a transcription factor essential for pluripotent stem cells and the development and maintenance of squamous epithelium. We previously reported SOX2 to be an oncogene subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here, we aim to further characterize SOX2's function in SCC. We demonstrate that SOX2 binds to distinct genomic loci in SCCs than in embryonic stem (ES) cells through comparative ChIP-seq analysis. Through mass-spectrometric analysis following tandem-affinity immunopurification in SCCs we identify SOX2 interacts with another master squamous transcription factor, p63, instead of its partner in ES cells, OCT4. We find that genomic occupancy of SOX2 in SCC overlaps with that of p63 at a large number of loci and this SOX2-p63 coordinate binding is absent in ES cells. We further demonstrate that SOX2 and p63 jointly regulate gene expression, including the oncogene ETV4, which we find essential for SOX2-amplified SCC cell survival. Together, these findings demonstrate that SOX2's actions in SCC differ substantially from its role in pluripotency. The identification of novel SOX2-p63 interaction enables deeper characterization of SOX2's function in SCC and normal squamous epithelial physiology.

Citation Format: Hideo Watanabe, Qiuping Ma, Shouyong Peng, Guillaume Adelmant, Danielle Swain, Wenyu Song, Cameron Fox, Joshua M. Francis, Chandra Sekhar Pedamallu, David S. Deluca, Angela N. Brooks, Jianwen Que, Anil K. Rustgi, Kwok-kin Wong, Keith L. Ligon, X. Shirley Liu, Jarrod A. Marto, Matthew Meyerson, Adam J. Bass. SOX2-p63 interaction and genomic co-localization in squamous cell carcinomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1391. doi:10.1158/1538-7445.AM2014-1391