NT5DC2 promotes leiomyosarcoma tumour cell growth via stabilizing unpalmitoylated TEAD4 and generating a positive feedback loop.
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SUBMITTER: Hu B
PROVIDER: S-EPMC8366447 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Backgroundγ-Glutamylcyclotransferase (GGCT), an enzyme crucial in glutathione metabolism, has emerged as a participant in tumorigenesis. The present study is designed to elucidate the biological role and molecular mechanisms underlying GGCT in glioma.MethodsGene Expression Profiling Interactive Analysis (GEPIA), Chinese Glioma Genome Atlas (CGGA), and PrognoScan online databases were utilized to examine the expressions and clinical prognosis of GGCT and REST in glioma. Cell Counting Kit-8 (CCK-8), Transwell, Wound healing, and Flow cytometric assays, and RNA-sequencing analysis were employed to uncover the molecular role of GGCT and REST. Prediction of Differentially expressed microRNA (DE-miRNAs) and miRNAs targeting GGCT 3' Untranslated Region (UTR) was performed using miRanda online datasets. Finally, Real time-quantitative Polymerase Chain Reaction (RT-qPCR), western blot and dual luciferase reporter gene activity analysis were employed to confirm a positive feedback loop involving GGCT/REST/miR-34a-5p in glioma cells.ResultsHigh expression of GGCT was correlated with poor prognosis in glioma. GGCT silencing demonstrated inhibitory effects on the proliferation, migration, and induction of apoptosis in T98G and U251 cells. Mechanistically, GGCT downregulated REST expression and modulated cancer-associated pathways in glioma cells. High expression of REST was associated with poor prognosis in glioma. In vitro and in vivo experiments showed that REST overexpression restored the repression of proliferation, invasion, migration, and xenograft tumor formation induced by GGCT knockdown. Furthermore, the study uncovered that REST inhibited miR-34a-5p mRNA expression, and miR-34a-5p suppressed GGCT expression by targeting its 3'UTR, forming a positive regulatory loop in glioma. Notably, the inhibitor of miR-34a-5p restored the role of REST silencing in decreasing GGCT expression in glioma cells.ConclusionsGGCT/REST/miR-34a-5p axis holds promising potential as a therapeutic target, offering a potential breakthrough in the treatment of glioma.
| S-EPMC11366900 | biostudies-literature
Project description:Potential functions of pseudogenes on tumorigenesis and development of human malignancies have been gradually revealed recently. However, the specific regulation and intracellular events associated with pseudogenes have not been illustrated clearly in hepatocellular carcinoma (HCC). AKR1B10P1 is an isoform pseudogene of oncogenic AKR1B10, and is barely transcribed in normal hepatocytes. In this study, anomalous transcript of AKR1B10P1 was detected in both HCC tissues and cell lines, and is positively correlated with its parental genes. High level of AKR1B10P1 transcript is correlated with dismal clinicopathologic features, including large tumor dimension, high level of serum Alpha-fetoprotein (AFP), advanced TNM stages, tumor microsatellite formation and venous invasion. Loss-of and gain-of function assays demonstrated the exact impact of AKR1B10P1 on promoting HCC cell proliferation. Furthermore, transcription factor SOX4 was discovered facilitating the activation of AKR1B10P1 transcription, and was validated as a down-stream target degraded by tumor-suppressing miR-138. Meanwhile, we discovered the existence of a positive feedback from AKR1B10P1, by which miR-138 interacts with AKR1B10P1 via a competing endogenous RNA (ceRNA) way. Thus, we suggest a positive feedback loop of AKR1B10P1/miR-138/SOX4, promoting HCC cell proliferation. In summary, the AKR1B10P1/miR-138/SOX4 loop in HCC cells provides us potential and probable targets contributing to HCC prevention and therapeutic treatment.
| S-EPMC7540089 | biostudies-literature
Project description:Dickkopf1 (DKK1) is overexpressed in various cancers and promotes cancer cell proliferation by binding to cytoskeleton-associated protein 4 (CKAP4). However, the mechanisms underlying DKK1 expression are poorly understood. RNA sequence analysis revealed that expression of the transcription factor forkhead box M1 (FOXM1) and its target genes concordantly fluctuated with expression of DKK1 in pancreatic ductal adenocarcinoma (PDAC) cells. DKK1 knockdown decreased FOXM1 expression and vice versa in PDAC and esophageal squamous cell carcinoma (ESCC) cells. Inhibition of either the DKK1-CKAP4-AKT pathway or the ERK pathway suppressed FOXM1 expression, and simultaneous inhibition of both pathways showed synergistic effects. A FOXM1 binding site was identified in the 5'-untranslated region of the DKK1 gene, and its depletion decreased DKK1 expression and cancer cell proliferation. Clinicopathological and database analysis revealed that PDAC and ESCC patients who simultaneously express DKK1 and FOXM1 have a poorer prognosis. Multivariate analysis demonstrated that expression of both DKK1 and FOXM1 is the independent prognostic factor in ESCC patients. Although it has been reported that FOXM1 enhances Wnt signaling, FOXM1 induced DKK1 expression independently of Wnt signaling in PDAC and ESCC cells. These results suggest that DKK1 and FOXM1 create a positive feedback loop to promote cancer cell proliferation.
| S-EPMC8249240 | biostudies-literature
Project description:High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator proteins that were conserved across independent cohorts. A 10-protein transcriptional module-centered around a TEAD4-MYCN positive feedback loop-emerged as the regulatory driver of the high-risk subtype associated with MYCN amplification. Silencing of either gene collapsed MYCN-amplified (MYCNAmp) neuroblastoma transcriptional hallmarks and abrogated viability in vitro and in vivo Consistently, TEAD4 emerged as a robust prognostic marker of poor survival, with activity independent of the canonical Hippo pathway transcriptional coactivators YAP and TAZ. These results suggest novel therapeutic strategies for the large subset of MYCN-deregulated neuroblastomas.Significance: Despite progress in understanding of neuroblastoma genetics, little progress has been made toward personalized treatment. Here, we present a framework to determine the downstream effectors of the genetic alterations sustaining neuroblastoma subtypes, which can be easily extended to other tumor types. We show the critical effect of disrupting a 10-protein module centered around a YAP/TAZ-independent TEAD4-MYCN positive feedback loop in MYCNAmp neuroblastomas, nominating TEAD4 as a novel candidate for therapeutic intervention. Cancer Discov; 8(5); 582-99. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 517.
| S-EPMC5967627 | biostudies-literature
Project description:zong non-coding RNAs (lncRNAs) have been identified as crucial effector in modulating the progression of assorted malignancies. In our study, the main aim was to unveil the role and the underlying regulatory mechanism of long intergenic non-protein coding RNA 1605 (LINC01605) in nasopharyngeal carcinoma (NPC). RT-qPCR analysis results suggested that LINC01605 was upregulated in NPC cells. According to the results of function experiments, LINC01605 promoted NPC cell proliferation and impeded cell apoptosis. The oncogenic role of LINC01605 in NPC was further validated by animal experiments. Additionally, we verified that LINC01605 regulated Ikbkb expression to promote the nuclear translocation of p65 and thereby activated the NF-κB pathway in NPC cells. Mechanism experiments further suggested that LINC01605 could regulate Ikbkb expression via sponging miR-942-5p. Moreover, LINC01605 recruited IGF2BP2 to stabilize ubiquitin-specific protease 3 (USP3) mRNA and thereby enhanced the stability of IkB subunit beta (IKKβ) protein. In addition, p65 acted as a transcription activator to upregulate LINC01605 in NPC cells. In conclusion, this study demonstrated a positive feedback loop between LINC01605 and the NF-κB signalling pathway that promoted NPC cell growth, thus providing new insights to better understand NPC. [Figure: see text].
| S-EPMC8986260 | biostudies-literature
Project description:Accumulating evidences revealed that long noncoding RNAs (lncRNAs) are frequently implicated in non-small cell lung cancer (NSCLC). Herein, we reported the identification of a novel NSCLC-associated functional lncRNA ZNF205 antisense RNA 1 (ZNF205-AS1). ZNF205-AS1 was increased in NSCLC tissues and cell lines, and associated with poor prognosis of NSCLC patients. Bioinformatics prediction, combined with experimental verification revealed that early growth response 4 (EGR4) directly bound to ZNF205-AS1 promoter, increased the promoter activity of ZNF205-AS1, and activated ZNF205-AS1 transcription. Intriguingly, ZNF205-AS1 transcript directly interacted with EGR4 mRNA, increased EGR4 mRNA stability, and up-regulated EGR4 expression via RNA-RNA interaction. Thus, ZNF205-AS1 and EGR4 formed a positive feedback loop. Through regulating EGR4, ZNF205-AS1 activated its own promoter activity. EGR4 was also increased in NSCLC and the expression of ZNF205-AS1 was significantly positively correlated with EGR4 in NSCLC tissues. Gain-of-function and loss-of-function assays demonstrated that both ZNF205-AS1 and EGR4 promoted NSCLC cell growth in vitro and NSCLC tumour growth in vivo. Concurrently depleting ZNF205-AS1 and EGR4 more significantly repressed NSCLC tumour growth in vivo. Collectively, our study demonstrated that the positive feedback loop between ZNF205-AS1 and EGR4 promotes NSCLC growth, and implied that targeting this feedback loop may be promising therapeutic strategy for NSCLC.
| S-EPMC6349159 | biostudies-literature
Project description:It is prevailingly thought that estrogen signaling is not involved in development of estrogen receptor (ER)-negative breast cancer. However, there is evidence indicating that ovariectomy prevents the development of both ER-positive and -negative breast cancer, suggesting that estrogen signaling is involved in the development of ER-negative breast cancer. Previously, our laboratory cloned a variant of ER-?, ER-?36, and found that ER-?36 mediated nongenomic estrogen signaling and is highly expressed in ER-negative breast cancer cells. In this study, we found that ER-?36 was highly expressed in 10/12 cases of triple-negative breast cancer. We investigated the role of mitogenic estrogen signaling mediated by ER-?36 in malignant growth of triple-negative breast cancer MDA-MB-231 and MDA-MB-436 cells that express high levels of ER-?36 and found that these cells strongly responded to mitogenic estrogen signaling both in vitro and in vivo. Knockdown of ER-?36 expression in these cells using the small hairpin RNA method diminished their responsiveness to estrogen. ER-?36 physically interacted with the EGFR/Src/Shc complex and mediated estrogen-induced phosphorylation of epidermal growth factor receptor (EGFR) and Src. EGFR signaling activated ER-?36 transcription through an AP1 site in the ER-?36 promoter, and ER-?36 expression was able to stabilize EGFR protein. Our results, thus demonstrated that ER-?36 mediates nongenomic estrogen signaling through the EGFR/Src/ERK signaling pathway in ER-negative breast cancer cells and suggested that a subset of ER-negative breast tumors that expresses ER-?36, retains responsiveness to mitogenic estrogen signaling.
| S-EPMC3020987 | biostudies-literature
Project description:BackgroundHepatitis B Virus (HBV) contributes to liver carcinogenesis via various epigenetic mechanisms. The newly defined epigenetics, epitranscriptomics regulation, has been reported to involve in multiple cancers including Hepatocellular Carcinoma (HCC). Our previous study found that HBx, HBV encodes X protein, mediated H3K4me3 modification in WDR5-dependent manner to involve in HBV infection and contribute to oncogene expression. AlkB Homolog 5 (ALKBH5), one of epitranscriptomics enzymes, has been identified to be associated with various cancers. However, whether and how ALKBH5 is dysregulated in HBV-related HCC remains unclear yet. This study aims to investigate ALKBH5 function, clinical significance and mechanism in HBV related HCC (HBV-HCC) patients derived from Chinese people.MethodsThe expression pattern of ALKBH5 was evaluated by RT-qPCR, Western blot, data mining and immunohistochemistry in total of 373 HBV-HCC tissues and four HCC cell lines. Cell Counting Kit 8 (CCK8) assay, Transwell and nude mouse model were performed to assess ALKBH5 function by both small interference RNAs and lentiviral particles. The regulation mechanism of ALKBH5 was determined in HBx and WDR5 knockdown cells by CHIP-qPCR. The role of ALKBH5 in HBx mRNA N6-methyladenosine (m6A) modification was further evaluated by MeRIP-qPCR and Actinomycin D inhibitor experiment in HBV-driven cells and HBx overexpression cells.ResultALKBH5 increased in tumor tissues and predicts a poor prognosis of HBV-HCC. Mechanically, the highly expressed ALKBH5 is induced by HBx-mediated H3K4me3 modification of ALKBH5 gene promoter in a WDR5-dependent manner after HBV infection. The increased ALKBH5 protein catalyzes the m6A demethylation of HBx mRNA, thus stabilizing and favoring a higher HBx expression level. Furthermore, there are positive correlations between HBx and ALKBH5 in HBV-HCC tissues, and depletion of ALKBH5 significantly inhibits HBV-driven tumor cells' growth and migration in vitro and in vivo.ConclusionsHBx-ALKBH5 may form a positive-feedback loop to involve in the HBV-induced liver carcinogenesis, and targeting the loop at ALKBH5 may provide a potential way for HBV-HCC treatment.
| S-EPMC8194239 | biostudies-literature
Project description:Tob1, a Tob/BTG anti-proliferative protein family member, functions as a tumour suppressor in many cancers. Here, we reveal a unique oncogenic role of Tob1 in colon cancer. Tob1 expression was upregulated during colon cancer progression, was significantly correlated with tumour size and tumour differentiation, and was a prognostic indicator of colon cancer. Unlike in other cancers, where nuclear Tob1 performs anticancer activity, Tob1 is predominantly localized in the cytosol of colon cancer cells, where this protein binds and stabilizes β-catenin to activate Wnt/β-catenin signalling, which in turn enhances Tob1 expression, thus forming a positive feedback loop to promote cell proliferation. Moreover, Tob1 deficiency led to reduced tumourigenesis in AOM/DSS-treated and ApcMin/+ mice. Our findings provide important insights into a previously unrecognized oncogenic role of Tob1 in colon cancer and suggest that Tob1 is an adverse prognostic factor and therapeutic target for colon cancer.
| S-EPMC6240287 | biostudies-literature
Project description:Backgroundt(8;21)(q22;q22) is one of the most frequent chromosomal abnormalities in acute myeloid leukemia (AML), leading to the generation of the fusion protein AML1-ETO. Despite t(8;21) AML being considered as a subtype with a favorable prognosis, approximately 30-50% of patients experience drug resistance and subsequent relapse. N6-methyladenosine (m6A) is demonstrated to be involved in the development of AML. However, the regulatory mechanisms between AML1-ETO and m6A-related enzymes and the roles of dysregulated m6A modifications in the t(8;21)-leukemogenesis and chemoresistance remain elusive.MethodsChromatin immunoprecipitation, dual-luciferase reporter assay, m6A-qPCR, RNA immunoprecipitation, and RNA stability assay were used to investigate a regulatory loop between AML1-ETO and FTO, an m6A demethylase. Gain- and loss-of-function experiments both in vitro and in vivo were further performed. Transcriptome-wide RNA sequencing and m6A sequencing were conducted to identify the potential targets of FTO.ResultsHere we show that FTO is highly expressed in t(8;21) AML, especially in patients with primary refractory disease. The expression of FTO is positively correlated with AML1-ETO, which is attributed to a positive regulatory loop between the AML1-ETO and FTO. Mechanistically, AML1-ETO upregulates FTO expression through inhibiting the transcriptional repression of FTO mediated by PU.1. Meanwhile, FTO promotes the expression of AML1-ETO by inhibiting YTHDF2-mediated AML1-ETO mRNA decay. Inactivation of FTO significantly suppresses cell proliferation, promotes cell differentiation and renders resistant t(8;21) AML cells sensitive to Ara-C. FTO exerts functions by regulating its mRNA targets, especially IGFBP2, in an m6A-dependent manner. Regain of Ara-C tolerance is observed when IGFBP2 is overexpressed in FTO-knockdown t(8;21) AML cells.ConclusionOur work reveals a therapeutic potential of targeting AML1-ETO/FTO/IGFBP2 minicircuitry in the treatment for t(8;21) patients with resistance to Ara-C.
| S-EPMC10807068 | biostudies-literature