UTX inhibition suppresses proliferation and promotes apoptosis in patient-derived glioblastoma stem cells by modulating periostin expression

Abstract Glioblastoma stem cells (GSCs) link tightly to glioblastoma (GBM) development, progression, therapeutic resistance and recurrence, suggesting GSCs as a novel target for drug discovery. UTX, a histone H3K27 demethylase, participates in regulating multiple cancer types. However, less is known about the function of UTX in GBM, let alone in GSCs. Our study aims to investigate the role and regulatory mechanism of UTX on GSCs. TCGA data showed that higher UTX expression was found in GBM and inversely correlated with survival. UTX inhibition hindered GBM cell growth and caused cell apoptosis. Subsequently, we cultured the primary GSCs, which were isolated from three patients. UTX inhibition suppressed cell proliferation and promoted apoptosis in GSCs. RNA-seq was performed to analyze the gene expression changes after silencing UTX in GSCs. The results indicated that UTX-mediated genes were strongly correlated with GBM progression and regulatory tumor microenvironment (TME). Transwell co-cultured experiment showed that silencing UTX in the transwell chamber GSCs could also inhibit the well plate cell proliferation. Protein-protein interaction analysis revealed that periostin (POSTN) played a role in the UTX-mediated transcriptional regulatory network. Replenishment of POSTN abolished the effect of UTX inhibition on GSCs proliferation and apoptosis, ablated the differential expression of intra- and extracellular levels of COL1A1 and VCAM1. Combining the above results together, our study demonstrated that UTX inhibition hindered POSTN expression by enhancing the H3K27me2/3 level, eventually resulting in inhibiting proliferation and promoting apoptosis of patient-derived GSCs. Our findings may provide a novel and effective strategy for the treatment of GBM.