Abstract A15: A reciprocal feedback loop between grainyhead-like-2 and ZEB1 controls EMT and tumor suppression

Abstract

Abstract The oncogenic Epithelial-Mesenchymal Transition (EMT) enhances malignant progression by promoting invasion and survival of tumor cells. EMT is induced by microenvironmental factors including TGF-β and Wnt agonists, and transcription factors including the E-box binding factors Twist, Snail and ZEB. Previously, we reported that a member of the mammalian Grainyhead family of wound healing-regulatory transcription factors, Grainyhead-like-2 (GRHL2), suppresses EMT and restores sensitivity to anoikis by repressing ZEB1 expression and inhibiting TGF-β signaling. Here, we elucidate the functional relationship between GRHL2 and ZEB1 in EMT/MET and tumor biology. At least three homeodomain proteins, Six1, LBX1, and HoxA5, transactivated the ZEB1 promoter; for Six1, this occurred through direct protein-promoter interaction. GRHL2 altered the Six1-DNA complex, inhibiting this transactivation. Correspondingly, GRHL2 expression prevented tumor initiation in xenograft assays, sensitized breast cancer cells to paclitaxel, and suppressed the emergence of CD44highCD24low cells in a cell line where this marker set correlates with cancer stem cell phenotype. GRHL2 was down-regulated in recurrent mouse tumors that had evolved to an oncogene-independent, EMT-like state, supporting a role for GRHL2 down-regulation in this tumor phenotype transition modeling disease recurrence. The combination of TGF-β and Wnt activation repressed GRHL2 expression through direct interaction of ZEB1 with the GRHL2 promoter, inducing EMT. These observations indicate that a reciprocal feedback loop between GRHL2 and ZEB1 controls epithelial vs. mesenchymal phenotypes and EMT-driven tumor progression. Citation Format: Benjamin Cieply, Heide L. Ford, Joshua Farris, Steven Frisch. A reciprocal feedback loop between grainyhead-like-2 and ZEB1 controls EMT and tumor suppression. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A15.