Abstract 3101: Pituitary homeobox 2 (PITX2) promotes thyroid carcinogenesis by activation of cyclin D2

Abstract

Abstract Pituitary homeobox 2 (PITX2), a Paired-like homeodomain transcription factor and a downstream effector of β-catenin signaling, plays substantial roles in normal embryonic development but its possible involvement in tumorigenesis was unknown. In this study, we extend its function in human cancer. Remarkably, we found that PITX2 was frequently overexpressed in human cancerous (papillary, follicular, and anaplastic) thyroid tissues, indicating for the first time that overactivated PITX2 may contribute to thyroid cancer. Cell-based and biochemical studies were performed to uncover the molecular mechanism of PITX2 action in thyroid cancer. Knockdown of PITX2 gene expression in human thyroid cancer cells significantly reduced cell proliferation and soft-agar colony formation. Biochemical analysis of cell cycle regulators upon PITX2 knockdown revealed down-regulation of all three D-type Cyclins (Cyclin D1, Cyclin D2 and Cyclin D3), dephosphorylation of Rb, and up-regulation of p15(INK4B) and p27(Kip1). Chromatin immunoprecipitation and promoter reporter assay indicated that Cyclin D2 was a direct target gene of PITX2. Consistently, we observed that high expression levels of Cyclin D2 were frequently associated with PITX2 overexpression in thyroid cancer tissues. To confirm our results in vivo, we took advantage of a mouse model of thyroid cancer (TRbetaPV/PV mouse). Consistently, the aberrant elevation of Pitx2 levels in the thyroid cancer of TRbetaPV/PV mice was accompanied by up-regulation of Cyclin Ds, increased phosphorylation of Rb, and down-regulation of p15(INK4B). Collectively, our findings demonstrate that the overactivated PITX2-Cyclin D2 pathway promotes thyroid tumorigenesis, and they provide the first evidence implicating an oncogenic role of PITX2 in human cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3101.