Ailanthone disturbs cross-talk between cancer cells and tumor-associated macrophages via HIF1-α/LINC01956/FUS/β-catenin signaling pathway in glioblastoma

Abstract Background An increasing number of studies have focused on ailanthone (aila) due to its antitumor activity. However, the role of ailanthone in glioblastoma(GBM) has not been investigated before. This study aims to explore the biological function and the underlying mechanism of ailanthone in GBM. Methods The microarray analysis was used to screen out down-stream long non-coding RNAs (lncRNAs) targeted by ailanthone. Real-time PCR(RT-PCR) assay was used to examine LINC01956 expression levels. Colony-formation, Methylthiazolyldiphenyl-tetrazolium bromide(MTT), cell-cycle, organoids culture and in-vivo tumorigenesis assays were used to examine cell growth in vitro and in vivo. Boyden assay was used to examine cell invasion ability in vitro. RNA immunoprecipitation and RNA-protein pull-down assays were used to examine the interaction between LINC01956 and FUS protein. Chromatin Immunoprecipitation(ChIP) assay was used to examine HIF1-α-binding sites in the LINC01956 promoter. Results Ailanthone decreased GBM cell growth in vitro and in vivo via inducing ferroptosis. Ailanthone treatment exhibited blood‒brain barrier(BBB) permeability and specifically targeted the tumor area. LINC01956 was identified as a down-stream target of Ailanthone. LINC01956 exerted as an onco-lncRNA in GBM. M2 polarization of macrophages induced by exosomes derived from glioma cells overexpressing LINC01956 accelerated GBM progression. Mechanistically, we found that LINC01956 bound to FUS and reduced its ubiquitination. LINC01956 evoked nuclear translocation of phosphorylated (p)-β-catenin by recruiting FUS. Furthermore, under hypoxic conditions, LINC01956 was regulated by HIF-1α. Ailanthone decreased the expression of LINC01956 via suppressing HIF-1α. Conclusion Taken together, our data revealed for the first time that ailanthone regulated HIF-1α/LINC01956/FUS/β-catenin signaling pathway and thereby inhibited GBM progression.