A positive feedforward circuit shaped by DLGAP5 and E2F1 triggers bladder cancer progression
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ABSTRACT:
PROVIDER: PRJNA1008582 | ENA |
REPOSITORIES: ENA
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Project description:Bladder cancer (BLCA) is a highly prevalent malignancy on a global scale, characterized by significant tumor heterogeneity. The investigation of molecular mechanisms that can be leveraged for the management of aggressive BLCA represents a particularly pertinent objective.DLGAP5 is mitosis-related protein widely existed in eukaryotic cells. The molecular mechanism of DLGAP5 in bladder cancer is still not clear, despite its role in tumorigenesis. Bladder cancer tissues exhibit a noteworthy increase in DLGAP5 expression, compared to normal bladder tissues. Furthermore, the expression of DLGAP5 shows a positive correlation with the clinical stage of the tumor and a negative impact on the prognosis. Cell proliferation and migration are significantly impacted by alterations in DLGAP5 expression, as demonstrated by in vitro and in vivo experiments. Further investigation reveals that DLGAP5 regulated E2F1 protein stability via USP11 deubiquitinase activity, and DLGAP5 is a direct target of E2F1. DLGAP5-E2F1 forms a positive feedback loop and influences the efficacy of BLCA progression. Collectively, DLGAP5 could potentially serve as a new therapeutic target for the treatment of bladder cancer.
2023-12-31 | GSE241523 | GEO
Project description:The dysregulation of transcription factors is widely associated with tumourigenesis. As the most well-defined transcription factor in multiple types of cancer, c-Myc can transform cells by transactivating various downstream genes. Given that there is no effective way to directly inhibit c-Myc, c-Myc targeting strategies hold great potential for cancer therapy. In this study, we found that WSB1, which has a highly positive correlation with c-Myc in 10 cancer cell lines and clinical samples, is a direct target gene of c-Myc, and can positively regulate c-Myc expression, which forms a feedforward circuit promoting cancer development. RNA sequencing results from Bel-7402 cells confirmed that WSB1 promoted c-Myc expression through the β-Catenin pathway. Mechanistically, WSB1 affected β-Catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptor β-TRCP recruitment, which inhibited the ubiquitination of β-Catenin and transactivated c-Myc. Of interest, the effect of WSB1 on c-Myc was independent of its E3 ligase activity. Moreover, overexpressing WSB1 in the Bel-7402 xenograft model could further strengthen the tumour-driven effect of c-Myc overexpression. Thus, our findings revealed a novel mechanism involved in tumourigenesis in which the WSB1/c-Myc feedforward circuit played an essential role, highlighting a potential c-Myc intervention strategy in cancer treatment.
2021-10-01 | GSE182635 | GEO
Project description:WSB1 regulates c-Myc expression through β-Catenin signalling and forms a feedforward circuit.
| PRJNA757243 | ENA
Project description:Rationale: A number of guanine nucleotide exchange factors (GEFs) including epithelial cell transforming factor ECT2 are believed to drive carcinogenesis through activating distinct oncogenic GTPases. Yet, whether GEF-independent activity of ECT2 also plays a role in tumorigenesis remains unclear. Methods: Immunohistochemical (IHC) staining, colony formation and xenograft assays were used to examine the role of ECT2 in breast carcinogenesis. Co-immunoprecipitation, immunofluorescent stainings, in vivo deubiquitination and in vitro deubiquitination experiments were performed to examine the physical and functional interaction between ECT2 and ubiquitin-specific protease USP7. High-throughput RNA sequencing, quantitative reverse transcription-PCR and Western blotting were employed to investigate the biological significance of the interplay between ECT2 and USP7. Results: We report that ECT2 plays a tumor-promoting role in breast cancer, and GEF activity-deficient ECT2 is able to alleviate ECT2 depletion associated growth defects in breast cancer cells. Mechanistically, we demonstrated that ECT2 physically interacts with ubiquitin-specific protease USP7 and functionally facilitates USP7 intermolecular self-association, -deubiquitination and -stabilization in a GEF activity-independent manner. USP7 in turn, deubiquitinates and stabilizes ECT2, resulting in a feedforward regulatory circuit that ultimately sustains the expression of oncogenic protein MDM2. Conclusion: Our study uncovers a GEF-independent role of ECT2 in promoting survival of breast cancer cells, provides a molecular insight for the reciprocal regulation of ECT2 and USP7, and supports the pursuit of ECT2/USP7 as potential targets for breast cancer intervention.
| S-EPMC7482815 | biostudies-literature
Project description:Bacteria selectively consume some carbon sources over others through a regulatory mechanism termed catabolite repression. Here, we show that the base pairing RNA Spot 42 plays a broad role in catabolite repression in Escherichia coli by directly repressing genes involved in central and secondary metabolism, redox balancing, and the consumption of diverse non-preferred carbon sources. Many of the genes repressed by Spot 42 are transcriptionally activated by the global regulator CRP. Since CRP represses Spot 42, these regulators participate in a specific regulatory circuit called a multi-output feedforward loop. We found that this loop can reduce leaky expression of target genes in the presence of glucose and can maintain repression of target genes under changing nutrient conditions. Our results suggest that base pairing RNAs in feedforward loops can help shape the steady-state levels and dynamics of gene expression. MG1655 lacIq cells harboring the control vector pBRplac or the Spot 42-inducible vector pSpot42 were grown in LB to an ABS600 of ~0.4 and treated with 1 mM IPTG. After 7 min, total RNA was isolated using the hot phenol extraction procedure.
2011-01-01 | E-GEOD-24875 | biostudies-arrayexpress
Project description:E2F transcription factors are known regulators of the cell cycle, proliferation, apoptosis and differentiation. We reveal an essential role for E2F1 in liver through the regulation of glycolysis and lipogenesis. E2F1 deficiency leads to a decreased in glycolysis and de novo synthesis of fatty acids in hepatocytes. ChIP-Seq was performed to determine direct tagets of E2F1 in hepatocytes. We highlight that E2F1 directly binds the promoters of genes implicated in metabolic process and notably key lipogenic genes to control these pathways.
2015-12-01 | GSE74006 | GEO
Project description:Although evidence indicates that the adult brain retains a considerable capacity for circuit formation, adult wiring has not been broadly considered and remains poorly understood. Here, we investigated wiring activation in adult neurons. Based on bioinformatic analyses on a previously published dataset (GSE161619), we identified the basic-helix-loop-helix (bHLH) transcription factor Ascl4 as a potential regulator of adult wiring and show that the AAV-mediated overexpression of Ascl4 can cell autonomously induce wiring in different types of hippocampal neurons of adult mice. The new axons are mainly feedforward and reconfigure synaptic weights in the hippocampal circuit. Mice with rewired circuits do not display signs of pathology and solve spatial problems equally well as controls. Our results demonstrate reprogrammed connectivity by a single transcriptional factor and provide insights into the regulation of brain connectivity in adults.
2024-05-09 | GSE246825 | GEO
Project description:Bacteria selectively consume some carbon sources over others through a regulatory mechanism termed catabolite repression. Here, we show that the base pairing RNA Spot 42 plays a broad role in catabolite repression in Escherichia coli by directly repressing genes involved in central and secondary metabolism, redox balancing, and the consumption of diverse non-preferred carbon sources. Many of the genes repressed by Spot 42 are transcriptionally activated by the global regulator CRP. Since CRP represses Spot 42, these regulators participate in a specific regulatory circuit called a multi-output feedforward loop. We found that this loop can reduce leaky expression of target genes in the presence of glucose and can maintain repression of target genes under changing nutrient conditions. Our results suggest that base pairing RNAs in feedforward loops can help shape the steady-state levels and dynamics of gene expression.
2011-01-01 | GSE24875 | GEO
Project description:Effect of FOXO knockdown on E2F1-mediated transcription
2012-07-06 | GSE39136 | GEO
Project description:Purpose: dose response analysis of E2F1 target genes expression in flow-sorted fractions with increasing amounts of fluorescently labled E2F1 Methods:U2OS pTRIPZ-YFP-ER-E2F1 cells were grown in full serum-containing growth medium and treated with 500 ng/ml doxycycline for 48 hours followed by addition of 90 nM OHT for an additional 20 hours. Cells from different YFP fractions were sorted by flow cytometry. mRNA profiles were generated by deep sequencing using Illumina HiSeq 4000. Results: different target genes have different E2F1 activation thresholds. Numerous proliferation-related target genes are induced already by the lowest E2F1-levels. Intermediate E2F1 levels induce cdk inhibitors, which might be responsible for cell cycle arrest. Finally, although some apoptotic E2F1 targets are induced already by low E2F1 levels, many key apoptotic genes require higher E2F1 levels for induction. Conclusions: induction of different cell fates by increasing E2F1 levels might pertain to differential affinities of the targets.
2017-08-22 | GSE93365 | GEO