Grainyhead-Like (GRHL2) Has Anti-Oncogenic Potential in Glioblastoma

Abstract

Grainyhead-like 2 (GRHL2) is a complex transcription factor associated with roles in both development and cancer. In development, GRHL2 suppresses a series of genes associated with the mesenchymal phenotype, while actively promoting the expression of genes associated with the epithelial phenotype. Due to this GRHL2 is considered a main gatekeeper of the epithelial to mesenchymal transition (EMT), playing a crucial role in epithelial morphogenesis and neural tube closure. These basic traits for GRHL2 have also been found to be similar in cancer. GRHL2 has multi-faceted functions in cancer, in which it can be considered either an oncogene or a tumor suppressor. In cancers where GRHL2 is overexpressed or mutated, GRHL2 functions as an oncogene, elevating expression through signaling cascades leading to the promotion of growth and invasion of cancer cells. Whereas, in the cancers where there is little to no expression of GRHL2, GRHL2 behaves as a tumor suppressor, when exogenously expressed. It does so by suppressing the mesenchymal phenotype while driving the epithelial phenotype and increasing the efficacy of therapeutic agents used to target tumor cells. The complex attributes of GRHL2 are highly dependent on the cell type and the different protein complexes available for GRHL2 to interact with.

Herein, I explore GRHL2 as it functions in glioblastoma (GBM). GBM is predominantly a mesenchymal or intermediate-mesenchymal cancer which strongly represses expression of GRHL2. A doxycycline-inducible GRHL2 construct was utilized to determine the overall effects of GRHL2 in GBM cell lines. These effects were then paired with the use of histone deacetylase inhibitors (HDACi) to determine the therapeutic outcome of GRHL2 expression in GBM. This dissertation also delves into GRHL2’s interactors, within the nucleus, in an effort to understand what GRHL2 cooperates with to bring about widespread repression of genes associated with the mesenchymal phenotype in GBM cells. Our findings demonstrate that GRHL2 actively suppresses mesenchymal genes through interactions with epigenetic machinery, such as HDAC1, while enhancing the therapeutic benefits of HDACi, through augmentation of cell death. Thus, GRHL2 has anti-oncogenic potential in GBM.