FLI1, circRNA FECR1, and ISG15 form feedback loop driving glioma malignancy and immunosuppression

Gliomas are aggressive primary brain tumors with a high degree of malignancy and poor prognosis, for which targeted therapeutics remain elusive in clinical practice. Current standard-of-care often involves surgery, radiation, and chemotherapy, but these treatments offer limited efficacy against the highly infiltrative and recurrent nature of these tumors. Understanding the intricate molecular mechanisms driving glioma progression and immune evasion is critical for identifying novel therapeutic targets. This study investigates a novel crosstalk circuitry involving the transcription factor FLI1, its associated circRNA, and an interferon-stimulated gene, aiming to uncover new vulnerabilities.

The study investigated the role of Friend leukemia virus integration 1 (FLI1) in glioma malignancy and immunomodulation. Researchers performed FLI1 knockdown in glioma cells to assess its impact on tumor phenotypes. They utilized RNA-seq and Co-IP assays to identify novel molecular targets of FLI1, specifically focusing on interferon-stimulated gene 15 (ISG15). Mechanistic studies explored FLI1's binding to the ISG15 promoter, its orchestration of intrachromosomal spatial loops, and associated epigenetic modifications including DNA hypomethylation and histone H3K9 and H3K27 acetylation. The team also examined the reciprocal feedback between FLI1 and ISG15, including ISG15's role in FLI1 stability.

Friend leukemia virus integration 1 (FLI1) was found to be upregulated in glioma, with its expression correlating with a malignant phenotype and poor prognosis. Aberrant FLI1 expression was regulated by its exonic circRNA FECR1 through a positive feedback mechanism. FLI1 knockdown effectively suppressed tumor phenotypes in glioma cells. Using RNA-seq and Co-IP assays, the study identified interferon-stimulated gene 15 (ISG15) as a novel molecular target of FLI1 in glioma. FLI1 coordinated with ISG15 to suppress immune function, significantly reducing the secretion of cytokines such as perforin, IFN-γ, TNF-α, and IL2 from T cells, as well as perforin from γδ T cells. Mechanistically, FLI1 bound to the ISG15 promoter regulatory elements, activating the ISG15 gene by orchestrating an active intrachromosomal spatial loop characterized by DNA hypomethylation and histone H3K9 and H3K27 acetylation.