RUNX1 contributes to the mesenchymal subtype of glioblastoma in a TGFβ pathway-dependent manner

Abstract

Runt-Related Transcription Factor 1 (RUNX1) is highly expressed in the Mesenchymal (Mes) subtype of glioblastoma (GBM). However, the specific molecular mechanism of RUNX1 in Mes GBM remains largely elusive. In this study, cell and tumor tissue typing were performed by RNA-sequencing. Co-immunoprecipitation (co-IP) and immunofluorescence (IF) were employed to identify members of the RUNX1 transcriptional protein complex. Bioinformatics analysis, chromatin immunoprecipitation (ChIP), and luciferase reporter experiments were utilized to verify target genes. Analyses of The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) verified the expression levels and prognoses associated with RUNX1/p-SMAD3/SUV39H1 target genes. In vivo patient-derived xenograft (PDX) studies and in vitro functional studies verified the impact of RUNX1 on the occurrence and development of GBM. The results showed that RUNX1 was upregulated in Mes GBM cell lines, tissues and patients and promoted proliferation and invasion in GBM in a TGFβ pathway-dependent manner in vivo and in vitro. We found and verified that BCL3 and MGP are transcriptionally activated by p-SMAD3 /RUNX1, while MXI1 is transcriptionally suppressed by the RUNX1/SUV39H1-H3K9me3 axis. This finding offers a theoretical rationale for using molecular markers and choosing therapeutic targets for the Mes type of GBM.

Screening and functional prediction of differentially expressed circular RNAs in human glioma of different grades

“…In addition, RUNX1 is considered to a key factor participating in the malignant biological behavior of glioma cells [ 40 ]. It is highly expressed and could contributes to the mesenchymal subtype of GBM in a TGFβ pathway-dependent manner [ 41 ]. Although many studies have analyzed the host genes of dysregulated circRNAs based on GO enrichment and pathway analyses [ 27 , 42 ], we support that GO and pathway analyses aimed at target genes can also better predict circRNA function.…”

Computational analysis and verification of molecular genetic targets for glioblastoma

“…For example, RNA regulatory factors can regulate the activity of microglia and participate in tumor progression and can act as a therapeutic target in GBM [9]. Runt-related transcription factor 1 (RUNX1) would impact the prognosis of GBM via the TGFβ pathway [10]. Therefore, it is important to further study the molecular mechanism of GBM and find targets for more effective early diagnosis and specific therapy.…”

Topical delivery of a small molecule RUNX1 transcription factor inhibitor for the treatment of proliferative vitreoretinopathy

“…Using our previously developed primary culture model of PVR and a newly developed PVR in vivo model, we successfully inhibited EMT and PVR progression via RUNX1 inhibition. To our knowledge this is the first report of successful preclinical modulation of a transcription factor to improve outcomes of an ocular condition driven by EMT 46 – 48 , 50 – 53 .…”

“…Binding of CBFβ to RUNX1 enhances RUNX1 binding of DNA initiating regulation of specific transcriptional targets 43 . In different contexts including hematopoiesis, vascular development, and cancer, among others, cells alternate between developmental fates using RUNX1 as a transcriptional switch to control cell proliferation, differentiation, survival, migration and invasion 42 , 44 – 48 . One of the most studied functions of RUNX1 relates to the process of endothelial to hematopoietic transition (EHT) where hemogenic endothelial cells become pre-hematopoietic stem and progenitor cells during embryogenesis 49 , 50 .…”

“…One of the most studied functions of RUNX1 relates to the process of endothelial to hematopoietic transition (EHT) where hemogenic endothelial cells become pre-hematopoietic stem and progenitor cells during embryogenesis 49 , 50 . However, many reports have been also published linking RUNX1 and EMT in non-ocular conditions 46 – 48 , 51 – 53 . Here we present evidence for RUNX1 as a master regulator of cell fates in EMT downstream TGF-β2 in PVR.…”