STEM-13. FUNCTIONAL CHARACTERIZATION OF THE ZFHX4-CHD4 INTERACTION IN GLIOBLASTOMA CANCER STEM CELLS

Glioblastoma stem cells (GSCs) they may be one reason for inevitable recurrence of GBM. We previously discovered that Zinc Finger Homeobox 4 (ZFHX4), a 450kD transcription factor, is required to maintain the GSC state. ZFHX4 interacts with CHD4, a core member of the nucleosome remodeling and deacetylase (NuRD) complex, which activates or represses gene expression via two distinct functions - histone deacetylation and ATP-dependent chromatin remodeling. CHD4 suppression phenocopies ZFHX4 suppression. The precise nature and function of the ZFHX4 interaction with CHD4 is not understood. Here we report that the ZFHX4-CHD4 interaction requires a single zinc-finger domain. An incremental truncation screen revealed that ZFHX4 amino acids 1838 to 2387, which contains zinc fingers 14 and 15, are required to bind CHD4. Disrupting the zinc coordination of zinc finger 14 impaired the ZFHX4-CHD4 interaction. Moreover, by overexpressing ZFHX4 amino acids 1838 to 2487, we decreased CHD4 recruitment to transcription regulatory regions of the stem cell genes SOX2 and SOX9, decreased transcription, and reduced clonogenic self-renewal. These results may provide the structural basis for new treatments to target GSCs and prevent recurrence in this devastating disease.