CELL INTELLIGENCE · 肿瘤细胞治疗研究

Gliomas comprise a group of common primary brain tumors with a high degree of malignancy and a poor prognosis. There are currently no targeted therapeutics for glioma in clinical practice. The present study revealed a novel crosstalk circuitry mechanism that contributes to the overexpression of Friend leukemia virus integration 1 ( FLI1 ) in glioma. FLI1 , a member of the ETS transcription factor family, was upregulated in glioma and its expression was associated with malignant phenotype and poor prognosis of the disease. Notably, aberrant FLI1 expression in glioma was regulated by its exonic circRNA FECR1 through a positive feedback mechanism. FLI1 knockdown suppresses tumor phenotypes of glioma cells. Using RNA‑seq and Co‑IP assays, the present study identified interferon‑stimulated gene 15 ( ISG15 ), a paracrine factor known to reprogram the tumor immunosuppressive microenvironment, as a new molecular target of FLI1 in glioma. FLI1 coordinated with ISG15 to suppress immune function, including the secretion of the cytokines 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, where it activates the ISG15 gene by orchestrating an active intrachromosomal spatial loop with characteristic DNA hypomethylation and histone H3K9 and H3K27 acetylation. As a downstream target, ISG15 also participated in a positive feedback loop with FLI1 by enhancing its stability from ubiquitination‑induced degradation. Thus, targeting this FLI1‑ISG15 feedback circuitry may provide a novel strategy to develop therapeutics for gliomas.