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Annexin 2A sustains glioblastoma cell dissemination and proliferation affecting patient prognosis

ABSTRACT: Glioblastoma (GBM) is the most devastating tumour of the brain, endowed with a fatal prognosis. Indeed, the complete eradication of cancer cell disseminated outside the GBM mass still remains a crucial issue. Given the reported strong association existing between Annexin 2A (ANXA2) expression and cell dissemination in many cancers, we evaluated the effects exerted by the modulation of ANXA2 levels in GBM cells and assessed its potential in predicting patient outcome. Here, we show that expression of ANXA2 positively correlates with metastatic gene signatures and demonstrates to be prognostic by itself. Indeed, we prove that ANXA2 is involved in cell migration, invasion, cytoskeletal remodeling and proliferation in GBM cells. Moreover, we were able to construct a gene signature representative of ANXA2 inhibition, which showed a significant prognostic potential in different GBM patient cohorts. In this study, we demonstrate that ANXA2 acts at multiple levels in determining the disseminating and aggressive behaviour of GBM tumours. In particular, we clearly show that ANXA2 is involved in determining a migrating and disseminating phenotype of GBM cells, in controlling specific cell cycle checkpoints and a cytoskeletal remodeling associated to cell movement. These data sustain the potential of ANXA2 as a possible target and strong prognostic factor in the future management of GBM patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE76786 | GEO | 2016/07/24

SECONDARY ACCESSION(S): PRJNA308587

REPOSITORIES: GEO

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Project description:Purpose: Enzymes catalyzing histone H3 lysine 9 (H3K9) methylation, such as SUV39H1, SUV39H2, SETDB1, SETDB2, EHMT1, and EHMT2, are individually linked to cancer progression. However, a comprehensive comparison and understanding of their characteristics and mechanisms in cancers is lacking. This study aims to fill this knowledge gap and explore its translational implications. Experimental Design: We conducted multi-omics analyses, including gene expression, mutations, copy number variations, and DNA methylation, to assess the expression patterns, regulation, and prognostic relevance of H3K9 methyltransferases across tumor types. This led to the development of "H3K9me3 MtSig", incorporating SUV39H1, SUV39H2, and SETDB1, with a focus on GBM. Correlations with signaling pathways were explored using gene set enrichment analysis (GSEA) and single-cell expression analyses. ChIP-sequencing was employed to detect H3K9me3 genomic binding sites in GBM cells. We validated the dependency of H3K9me3 MtSig in GBM using patient-derived samples through western blot, immunohistochemistry, immunofluorescence, cell growth, and quantitative PCR. Clinical prediction modeling and drug susceptibility screening were utilized to identify potential therapeutic avenues. Results: H3K9 methyltransferases display diverse expression patterns across cancers, influenced by mutations, CNVs, and DNA methylation associated with the genes. The unique H3K9me3 MtSig signature shows prognostic implications and associations with signaling pathways, particularly in GBM. Elevated H3K9me3 MtSig levels in GBM cells correlate with the G2/M cell cycle positively and immune responses negatively. H3K9me3-mediated repetitive sequence silencing contributes to these phenotypes, with inhibiting it suppressing proliferation and enhancing immune responses. Clinically, H3K9me3 MtSig could act as an independent prognostic factor, and drug susceptibility screening identifies potential GBM biomarkers and therapeutics. Conclusions: H3K9me3 MtSig has the potential to elucidate novel prognostic markers, therapeutic targets, and predictors of treatment response in GBM and other cancer types for clinical intervention.

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Annexin 2A sustains glioblastoma cell dissemination and proliferation affecting patient prognosis

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