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CRISPR activation screen identifies GNAO1 as a driver of glioblastoma cell differentiation

ABSTRACT: Inducing tumor cell differentiation is a potential strategy for treating malignant cancers, including glioma. Here we perform a genome-scale CRISPR activation screen and identify that G Protein Subunit Alpha O1 (GNAO1) as a critical regulator of glioma cell differentiation. GNAO1 overexpression in combination with a small molecular inhibitor cocktail, including CHIR99021, SB431542, RepSox, and Y27632, markedly promotes neuronal differentiation of glioblastoma cells. GNAO1 is high expressed in normal neuronal tissues but low expressed in gliomas. High expression of GNAO1 is correlated with a better prognosis. GNAO1 overexpression decreases cell proliferation, cell migration, and orthotopic GBM tumor xenograft growth. GNAO1 overexpression activates neuronal differentiation pathways by down-regulation of transcript factor HES1, a key mediator of neuronal differentiation. GNAO1 recruits TRIM21 and increases TRIM21-mediated ubiquitination and degradation of CREB, leading to decreased p300-mediated H3K27ac levels of HES1 promoter and HES1 downregulation. In addition, GNAO1 mRNA stability is regulated by METTL3-regulated N6-methyladenosine (m6A). Overexpression of GNAO1 enhances glioblastoma response to Temozolomide (TMZ) and extends the survivals of animals bearing orthotopic GBM xenograft tumors. Our finding suggests that inducing neuronal differentiation of glioblastoma cells by engineering GNAO1 overexpression is a potential therapy strategy, which not only reduces tumor cell proliferation but also enhances tumor cell response to chemotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234341 | GEO | 2026/01/07

REPOSITORIES: GEO

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Project description:Glioblastoma (GBM) heterogeneity in the genomic and phenotypic properties has potentiated personalized approach against specific therapeutic targets of each GBM patient. The Cancer Genome Atlas (TCGA) Research Network has been established the comprehensive genomic abnormalities of GBM, which sub-classified GBMs into 4 different molecular subtypes. The molecular subtypes could be utilized to develop personalized treatment strategy for each subtype. We applied a classifying method, NTP (Nearest Template Prediction) method to determine molecular subtype of each GBM patient and corresponding orthotopic xenograft animal model. The models were derived from GBM cells dissociated from patient's surgical sample. Specific drug candidates for each subtype were selected using an integrated pharmacological network database (PharmDB), which link drugs with subtype specific genes. Treatment effects of the drug candidates were determined by in vitro limiting dilution assay using patient-derived GBM cells primarily cultured from orthotopic xenograft tumors. The consistent identification of molecular subtype by the NTP method was validated using TCGA database. When subtypes were determined by the NTP method, orthotopic xenograft animal models faithfully maintained the molecular subtypes of parental tumors. Subtype specific drugs not only showed significant inhibition effects on the in vitro clonogenicity of patient-derived GBM cells but also synergistically reversed temozolomide resistance of MGMT-unmethylated patient-derived GBM cells. However, inhibitory effects on the clonogenicity were not totally subtype-specific. Personalized treatment approach based on genetic characteristics of each GBM could make better treatment outcomes of GBMs, although more sophisticated classifying techniques and subtype specific drugs need to be further elucidated. Gene expression profiling experiments were conducted for 25 patient-derived xenograft glioblastoma samples using Affymetrix Human Gene 1.0 ST arrays according to manufacturer's protocol.

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CRISPR activation screen identifies GNAO1 as a driver of glioblastoma cell differentiation

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