Stxbp4 Suppresses Apc/C Mediated Turnover Of P63 And Increases Tumorigenicity And Malignancy

p63 plays a pivotal role in epithelial development and maintenance of epithelial proliferative potential. The delN isoforms of p63 are thought to be involved in both basal-epidermal gene expression and maintenance of epithelial progenitor proliferative potential. It is also thought that delN versions of p63 and p73 can serve to inhibit the abilities of their TA isoform counterparts to induce cell cycle arrest and apoptosis. Consistent with this, after DNA damage or during terminal differentiation, delNp63 proteins are quickly down regulated. Although p53 is frequently mutated in human cancers, p63 mutation is rare and it overexpresses especially in squamous carcinomas, such as lung, bladder, breast, and head and neck squamous cell carcinoma. Indeed several report concluded that immuno histochemistry with delNp63 is a powerful ancillary method for classifying lung adenocarcinoma and squamous carcinoma, a distinction with important therapeutic implications. We previously reported that APC/C plays a role in ubiquitin-mediated turnover of delNp63 and that Stxbp4 suppresses the degradation of delNp63 by the APC/C and Rack1-VHL. Importantly, both Stxbp4 and APC/C degradation-resistant delNp63 suppress the terminal differentiation process in 3D organotypic culture model as well as in vitro culture. To investigate the effect and the mechanism of delNp63 for tumorigenicity and malignancy in Lung squamous carcinoma, we examined a transcriptome analysis (RNA-seq) of delNp63 and Stxbp4 with NGS (Next Generation Sequencer) and generated xenograft mice model. Thus, our study provides insight into a novel mechanism for delNp63 in regulating tumorigenicity and malignancy in squamous cell carcinoma as well as epitherial development. Citation Format: Yukihiro Otaka, Susumu Rokudai, Kyoichi Kaira, Kimihiro Shimizu, Masashi Ito, Ami Ichihara, Reika Kawabata, Shinji Yoshiyama, Arito Yamane, Takayuki Asao, Carol Prives, Masahiko Nishiyama. Stxbp4 suppresses APC/C mediated turnover of p63 and increases tumorigenicity and malignancy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2070. doi:10.1158/1538-7445.AM2015-2070