Distinct functions of wild-type and mutant Δ133p53α R273H differentially regulate glioblastoma aggressiveness and therapy-induced senescence

ABSTRACT: Mutations effects on p53 isoforms’ activities remain largely unknown, although they are mutated in 92% of TP53 mutant cancers. Therefore, exploring the effect of mutations on p53 isoforms activities is a critical, albeit unexplored area in the p53 field. Current glioblastoma treatments, including temozolomide chemotherapy and radiations, induce cellular senescence through a p53-dependent mechanism. Nevertheless, GBMs still have a poor 6.8% five-year survival indicating a need to better understand underlying mechanisms affecting the response to treatments. The progression from low-grade astrocytoma to glioblastoma is accompanied by TP53 mutations. Since Δ133p53α prevents cellular senescence, studying the impact of its mutation in glioblastoma is relevant to determine if it affects the progression and response to treatment of GBM cells. In this aim, we stably overexpressed wild-type (WT) Δ133p53α in WT glioblastoma multiforme (GBM) cells, and Δ133p53α R273H in R273H mutant GBM cells. We used mRNA-sequencing to identify mutant Δ133p53α-specific target genes. We examined proliferation, invasion, DNA repair, apoptosis, and senescence regulation by WT and mutant Δ133p53α. All results were confirmed by siRNA knock-down. Finally, using TCGA data, we investigated the association of the mutant Δ133p53α-specific target genes to clinical outcome of GBM and low-grade glioma (LGG) patients. This study provides the first and most in-depth characterization of a mutant p53 isoform’s activities to date and demonstrate that mutant Δ133p53α R273H is an active contributor to glioblastoma carcinogenesis and response to treatment. Furthermore, by discovering the link between TP53 mutation and IL4I1/IDO1/AhR pathway, we show strong evidence of Δ133p53α R273H clinical relevance in mutant TP53 glioblastoma development and aggressiveness, and as a potential therapeutic target and biomarker.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240377 | GEO | 2024/07/31

REPOSITORIES: GEO