Histone Demethylase UTX/KDM6A Regulates Glioblastoma Progression Through Modulating the Tumor Microenvironment

Abstract

Background: UTX is strongly associated with multiple types of cancer. However, less is known about the function of UTX in glioblastoma (GBM). The study aims to define the effect of UTX on GBM. Methods: The UTX expression was compared in GBM and normal group by using GEPIA 2, and knockdown UTX by using UTX shRNA in GBM cell lines. The function of UTX on anti-tumor properties were examined through methods of BrdU incorporation, Flow cytometry analysis, TUNEL assay, western blotting analysis, ELISA, wound healing assay, transwell invasion analysis and xenograft experiment. Gene expression programs of UTX knockdown in GBM was analyzed by RNA-seq, qPCR and ChIP-qPCR. Findings: UTX knockdown in LN229 and U251 MG cells (both human GBM cell lines) inhibited proliferation, migration and invasion and promoted apoptosis. In the heterotopic xenograft model, UTX knockdown hampered tumor growth. Lots of genes were altered by UTX knockdown, most of them were closely associated with tumor progression and extracellular environment, which was represented as reduction of periostin (POSTN), COL1A1 and VCAM1 secretion. Addition of POSTN in the medium abolished the effect of UTX knockdown. Furthermore, UTX knockdown reduced the numbers of glioblastoma stem cells, while the number is partially restored after POSTN supplement. Interpretation: UTX regulated GBM progression through modulating the tumor microenvironment. Our findings may reveal new insight into the onset of gliomagenesis and progression, provide a vigorous therapeutic strategy for GBM treatment. Funding: National Natural Science Foundation of China (No. 81901156, 82001493); China Postdoctoral Science Foundation (2017M623152, 2018T111035, 2019M653662). Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: All mouse experiments were approved by the Xi’an Jiaotong University Health Science Center Ethics Committee. The mice were purchased from the Xi’an Jiaotong University Laboratory Animal Center (Certificate No. 22-9601018).