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Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression.

ABSTRACT: Myelin transcription factor 1 (Myt1) and Myt1l (Myt1-like) are zinc finger transcription factors that regulate neuronal differentiation. Reduced Myt1l expression has been implicated in glioblastoma (GBM), and the related St18 was originally identified as a potential tumor suppressor for breast cancer. We previously analyzed changes in gene expression in a human GBM cell line with re-expression of either Myt1 or Myt1l. This revealed largely overlapping gene expression changes, suggesting similar function in these cells. Here we show that re-expression of Myt1 or Myt1l reduces proliferation in two different GBM cell lines, activates gene expression programs associated with neuronal differentiation, and limits expression of proliferative and epithelial to mesenchymal transition gene-sets. Consistent with this, expression of both MYT1 and MYT1L is lower in more aggressive glioma sub-types. Examination of the gene expression changes in cells expressing Myt1 or Myt1l suggests that both repress expression of the YAP1 transcriptional coactivator, which functions primarily in the Hippo signaling pathway. Expression of YAP1 and its target genes is reduced in Myt-expressing cells, and there is an inverse correlation between YAP1 and MYT1/MYT1L expression in human brain cancer datasets. Proliferation of GBM cell lines is reduced by lowering YAP1 expression and increased with YAP1 over-expression, which overcomes the anti-proliferative effect of Myt1/Myt1l expression. Finally we show that reducing YAP1 expression in a GBM cell line slows the growth of orthotopic tumor xenografts. Together, our data suggest that Myt1 and Myt1l directly repress expression of YAP1, a protein which promotes proliferation and GBM growth.

SUBMITTER: Melhuish TA

PROVIDER: S-EPMC6203443 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression.

Melhuish Tiffany A TA Kowalczyk Izabela I Manukyan Arkadi A Zhang Ying Y Shah Anant A Abounader Roger R Wotton David D

Biochimica et biophysica acta. Gene regulatory mechanisms 20181010 11

Myelin transcription factor 1 (Myt1) and Myt1l (Myt1-like) are zinc finger transcription factors that regulate neuronal differentiation. Reduced Myt1l expression has been implicated in glioblastoma (GBM), and the related St18 was originally identified as a potential tumor suppressor for breast cancer. We previously analyzed changes in gene expression in a human GBM cell line with re-expression of either Myt1 or Myt1l. This revealed largely overlapping gene expression changes, suggesting similar ...[more]

PMID: 30312684

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Project description:Normal differentiation and induced reprogramming require the activation of target cell programs and silencing of donor cell programs. In reprogramming, the same factors are often used to reprogram many different donor cell types. As most developmental repressors, such as RE1-silencing transcription factor (REST) and Groucho (also known as TLE), are considered lineage-specific repressors, it remains unclear how identical combinations of transcription factors can silence so many different donor programs. Distinct lineage repressors would have to be induced in different donor cell types. Here, by studying the reprogramming of mouse fibroblasts to neurons, we found that the pan neuron-specific transcription factor Myt1-like (Myt1l) exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. In agreement with its repressive function, the genomic binding sites of Myt1l are similar in neurons and fibroblasts and are preferentially in an open chromatin configuration. The Notch signalling pathway is repressed by Myt1l through silencing of several members, including Hes1. Acute knockdown of Myt1l in the developing mouse brain mimicked a Notch gain-of-function phenotype, suggesting that Myt1l allows newborn neurons to escape Notch activation during normal development. Depletion of Myt1l in primary postmitotic neurons de-repressed non-neuronal programs and impaired neuronal gene expression and function, indicating that many somatic lineage programs are actively and persistently repressed by Myt1l to maintain neuronal identity. It is now tempting to speculate that similar 'many-but-one' lineage repressors exist for other cell fates; such repressors, in combination with lineage-specific activators, would be prime candidates for use in reprogramming additional cell types.

Project description:Background: Although the diagnosis and treatment of glioblastoma (GBM) is significantly improved with recent progresses, there is still a large heterogeneity in therapeutic effects and overall survival. The aim of this study is to analyze gene expressions of transcription factors (TFs) in GBM so as to discover new tumor markers. Methods: Differentially expressed TFs are identified by data mining using public databases. The GBM transcriptome profile is downloaded from The Cancer Genome Atlas (TCGA). The nonnegative matrix factorization (NMF) method is used to cluster the differentially expressed genes to discover hub genes and signal pathways. The TFs affecting the prognosis of GBM are screened by univariate and multivariate COX regression analysis, and the receiver operating characteristic (ROC) curve is determined. The GBM hazard model and nomogram map are constructed by integrating the clinical data. Finally, the TFs involving potential signaling pathways in GBM are screened by Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Results: There are 68 differentially expressed TFs in GBM, of which 43 genes are upregulated and 25 genes are downregulated. NMF clustering analysis suggested that GBM patients are divided into three groups: Clusters A, B, and C. LHX2, MEOX2, SNAI2, and ZNF22 are identified from the above differential genes by univariate/multivariate regression analysis. The risk score of those four genes are calculated based on the beta coefficient of each gene, and we found that the predictive ability of the risk score gradually increased with the prolonged predicted termination time by time-dependent ROC curve analysis. The nomogram results have showed that the integration of risk score, age, gender, chemotherapy, radiotherapy, and 1p/19q can further improve predictive ability towards the survival of GBM. The pathways in cancer, phosphoinositide 3-kinases (PI3K)-Akt signaling, Hippo signaling, and proteoglycans, are highly enriched in high-risk groups by GSEA. These genes are mainly involved in cell migration, cell adhesion, epithelial-mesenchymal transition (EMT), cell cycle, and other signaling pathways by GO and KEGG analysis. Conclusion: The four-factor combined scoring model of LHX2, MEOX2, SNAI2, and ZNF22 can precisely predict the prognosis of patients with GBM.

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Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression.

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Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression.

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