PLX222000

GSE95027: ZNF131 suppresses centrosome fragmentation in Glioblastoma stem-like cells through regulation of HAUS5

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

To identify new Glioblastoma multiforme (GBM) therapeutic strategies, we previously performed genome-wide RNAi lethality screens in patient-derived GBM stem-like cells (GSCs) and neural progenitor cells (NPCs) to identify genes required for the self-renewal of GSC isolates, but which are dispensable for NPCs. Here we report the retest of the GSC-lethal gene ZNF131, which encodes a novel vertebrate-specific BTB domain zinc finger transcription factor that is broadly required for GSC viability. Examination of gene expression changes after ZNF131 knockdown (kd) revealed that ZNF131 activity notably promotes expression of Joubert Syndrome ciliopathy genes, including KIF7, NPHP1, and TMEM237, as well as HAUS5, a component of Augmin/HAUS complex that facilitates microtubule (MT) nucleation along the mitotic spindle. Of these genes only kd of HAUS5 displayed GSC-specific viability loss, and, critically, HAUS5 ectopic expression was sufficient to suppress viability defects of ZNF131 kd cells. Moreover, ZNF131 and HAUS5 kd phenocopied each other in GSCs, each causing: mitotic arrest, centrosome fragmentation, loss of Augmin/HAUS complex on the mitotic spindle, and loss of GSC self-renewal and tumor formation capacity. In control NPCs, we observed centrosome fragmentation and lethality only when HAUS5 kd was combined with kd of HAUS2 or HAUS4, two other Augmin complex members, demonstrating that the complex is essential in NPCs, but that GSCs have heightened requirement. Our results suggest that GSCs differentially rely on ZNF131-dependent expression of HAUS5 as well as the Augmin/HAUS complex activity to maintain the integrity of centrosome function and viability. We speculate that this requirement likely arises from aneuploidy frequently observed in late stage GBM tumors, rather than supernumerary centrosomes. SOURCE: Sonali Arora (sarora@fredhutch.org) - FHCRC