A single factor induces neuronal differentiation to suppress glioma cell growth

Abstract

Summary Aim Glioma, with fast growth and progression features, is the most common and aggressive tumor in the central nervous system and is essentially incurable. This study is aimed at inducing neuronal differentiation to suppress glioma cell growth with a single transcription factor. Methods Overexpression of transcription factor SRY (sex determining region Y)‐box 11 (SOX11) and Zic family member 1 (ZIC1) was, respectively, performed in glioma cells with lentivirus infection. CRISPR/Cas9 technology was used to knock out ZIC1 in U87 cells, and knockout efficiency was identified by Western blotting and Sanger sequencing. Cell cycle and apoptosis were detected by flow cytometry. The downstream targets of SOX11 were analyzed by Affymetrix GeneChip microarrays. qRT‐PCR and immunofluorescence technique were used to verify gene targets of genetically modified U87 cells. All the cells were imaged by a fluorescence microscope. Gene expression correlation analysis and overall survival analysis based on TCGA dataset are performed by GEPIA. Results We induced glioma cells into neuron‐like cells to suppress cell growth using a single transcription factor, SOX11 or ZIC1. Besides, we proved that there is a strong correlation between SOX11 and ZIC1. Our study revealed that SOX11 upregulates ZIC1 expression by binding with ZIC1 promoter, and ZIC1 partially mediates SOX11‐induced neuronal differentiation in U87 cells. However, SOX11 expression is not regulated by ZIC1. Moreover, high MAP2 expression means better overall survival in TCGA lower grade glioma. Conclusion This study revealed that glioma cells can be reprogrammed into neuron‐like cells using a single factor ZIC1, which may be a potential tumor suppressor gene for gliomas treatment.

The Role of Neurodevelopmental Pathways in Brain Tumors

“…Genetic loss of ATOH1 results in neurophysiological deficits, including a reduction in the size of the cerebellum and premature death due to dysregulated respiration resulting in apnea ( Rose et al, 2009 ). Like many bHLH TFs, ATOH1 itself is rarely mutated in brain tumors; its expression levels, however, are reported to be dysregulated in a number of brain tumor subtypes ( Fu et al, 2019 ). The role of ATOH1 in high-grade glioma has yet to be well-defined, although correlative relationships between high ATOH1 expression in the SHH-activated subtype of medulloblastoma have been reported ( Salsano et al, 2004 ).…”

miR‐221/222 suppression induced by activation of the cAMP/PKA/CREB1 pathway is required for cAMP‐induced bidirectional differentiation of glioma cells

“…Consistently, we also showed that activation of the interleukin (IL)‐6/Janus tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) axis contributed to cAMP‐induced expression of the astrocytic biomarker glial fibrillary acidic protein (GFAP) in gliomas [16]. Interestingly, recent studies demonstrated that glioma cells could be directly reprogrammed into terminal‐differentiated neurons by either transduction of neuron‐specific transcriptional factors [17–20] or treating with a small molecule cocktail [21,22], suggesting that the differentiation fate of glioma cells is highly plastic and could be driven by different stimuli. However, the cAMP agonist‐induced differentiation pattern and the underlying mechanisms of glioma are still incompletely understood.…”

Glioma facilitates the epileptic and tumor-suppressive gene expressions in the surrounding region

“…Sall1 (Spalt-Like Transcription Factor 1), which is expressed specifically in microglia and is associated with microglial activation, suppresses glioma cell proliferation and migration and may work as a functional tumor suppressor gene in glioma 26 , 27 . Zic1 (Zic family member 1) is associated with the suppression of glioma cell growth 28 . Plxnb3 (plexin-B3) inhibits cell migration and invasion induced by stimulation with its ligand Sema5A 29 .…”