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Regulatory factor X1 is a new tumor suppressive transcription factor that acts via direct downregulation of CD44 in glioblastoma.

ABSTRACT: BACKGROUND:The biological functions of regulatory factor (RF)X1, a transcription factor, are not known. Since the RFX1 gene is often epigenetically silenced and clusters of differentiation (CD)44 proteins that regulate cancer cell biology are increased in human glioblastomas, we designed this study to determine whether RFX1 could regulate CD44 expression in glioblastoma. METHODS:Regulatory factor X1 was overexpressed in 4 human glioblastoma cell lines. CD44 expression and cell proliferation, apoptosis, and invasion were assayed under in vitro conditions. In vivo growth of human glioblastoma xenografts was determined in mice. The expression of RFX1 and CD44 in human glioblastoma tissues was quantified. RESULTS:A putative RFX1 binding sequence existed in the first exon of the human CD44 gene. The transcription activity of the DNA fragment containing this putative sequence was decreased in cells overexpressing RFX1. Regulatory factor X1 bound to the CD44 gene in glioblastoma cells. It reduced CD44 expression and activated Akt and extracellular signal-regulated kinase, signaling molecules downstream of CD44 to regulate cell proliferation and survival. Overexpression of RFX1 inhibited the survival, proliferation, and transwell invasion of glioblastoma cells and in vivo growth of human glioblastoma xenografts. CD44 overexpression reversed RFX1 effects on cell proliferation. Finally, CD44 protein levels were inversely correlated with RFX1 protein levels in human glioblastoma tissues. CONCLUSIONS:These results suggest that RFX1 directly regulates CD44 expression. This mechanism may contribute to RFX1's effects on proliferation, survival, and invasion of glioblastoma cells. Our results provide initial evidence that RFX1 may be an important target/regulator of the malignancy of glioblastoma.

SUBMITTER: Feng C

PROVIDER: S-EPMC4096175 | biostudies-other | 2014 Aug

REPOSITORIES: biostudies-other

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Regulatory factor X1 is a new tumor suppressive transcription factor that acts via direct downregulation of CD44 in glioblastoma.

Feng Chenzhuo C Zhang Ying Y Yin Jinbo J Li Jun J Abounader Roger R Zuo Zhiyi Z

Neuro-oncology 20140212 8

<h4>Background</h4>The biological functions of regulatory factor (RF)X1, a transcription factor, are not known. Since the RFX1 gene is often epigenetically silenced and clusters of differentiation (CD)44 proteins that regulate cancer cell biology are increased in human glioblastomas, we designed this study to determine whether RFX1 could regulate CD44 expression in glioblastoma.<h4>Methods</h4>Regulatory factor X1 was overexpressed in 4 human glioblastoma cell lines. CD44 expression and cell pro ...[more]

PMID: 24526308

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Project description:Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in humans. Recent studies revealed that patterns of microRNA (miRNA) expression in GBM tissue samples are different from those in normal brain tissues, suggesting that a number of miRNAs play critical roles in the pathogenesis of GBM. However, little is yet known about which miRNAs play central roles in the pathology of GBM and their regulatory mechanisms of action. To address this issue, in this study, we systematically explored the main regulation format (feed-forward loops, FFLs) consisting of miRNAs, transcription factors (TFs) and their impacting GBM-related genes, and developed a computational approach to construct a miRNA-TF regulatory network. First, we compiled GBM-related miRNAs, GBM-related genes, and known human TFs. We then identified 1,128 3-node FFLs and 805 4-node FFLs with statistical significance. By merging these FFLs together, we constructed a comprehensive GBM-specific miRNA-TF mediated regulatory network. Then, from the network, we extracted a composite GBM-specific regulatory network. To illustrate the GBM-specific regulatory network is promising for identification of critical miRNA components, we specifically examined a Notch signaling pathway subnetwork. Our follow up topological and functional analyses of the subnetwork revealed that six miRNAs (miR-124, miR-137, miR-219-5p, miR-34a, miR-9, and miR-92b) might play important roles in GBM, including some results that are supported by previous studies. In this study, we have developed a computational framework to construct a miRNA-TF regulatory network and generated the first miRNA-TF regulatory network for GBM, providing a valuable resource for further understanding the complex regulatory mechanisms in GBM. The observation of critical miRNAs in the Notch signaling pathway, with partial verification from previous studies, demonstrates that our network-based approach is promising for the identification of new and important miRNAs in GBM and, potentially, other cancers.

Dataset Information

Regulatory factor X1 is a new tumor suppressive transcription factor that acts via direct downregulation of CD44 in glioblastoma.

Publications

Regulatory factor X1 is a new tumor suppressive transcription factor that acts via direct downregulation of CD44 in glioblastoma.

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