Abstract 1132: PAX6 drives cancer cells toward a stem like state via GLI-SOX2 signaling axis in lung adenocarcinoma

PAX6 is an essential transcription factor for embryonic stem cell maintenance, but its contribution to lung cancer stem cells (CSCs) remains unexplored. We demonstrate that PAX6 acts as an oncogene responsible for induction of cancer stemness properties and plays a biological role in tumor initiation and CSC expansion in lung adenocarcinoma (LUAD). Mechanistically, PAX6 activates Hedgehog-GLI signaling in a SMO-independent noncanonical manner, resulting in SOX2 upregulation directly by the binding of GLI to the proximal promoter region of the SOX2 gene. The overexpressed SOX2 enhances the expression of key pluripotent factors (OCT4 and NANOG) and suppresses differentiation lineage factors (HOPX and NKX2-1). Thus, PAX6 drives cancer cells toward a stem-like state via the GLI-SOX2 signaling axis in LUAD. In contrast, in the differentiated non-CSCs that represent most of the tumor cell population, PAX6 is transcriptionally silenced by its promoter methylation. In human lung cancer tissues, the positive linear correlations of PAX6 expression with GLI and SOX2 expression and its negative correlations with HOPX and NKX2-1 expression were observed. Therapeutically, the blockade of the PAX6-GLI-SOX2 signaling axis elicits a long-lasting therapeutic efficacy by limiting CSC expansion following chemotherapy. Our findings provide a rationale for targeting the PAX6-GLI-SOX2 signaling axis with chemotherapy as an effective therapeutic strategy. Citation Format: Akira Oki, Mohammad O. Hoque. PAX6 drives cancer cells toward a stem like state via GLI-SOX2 signaling axis in lung adenocarcinoma [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 1132.