Anti-Proliferative Effects of E2F1 Suppression in Glioblastoma Cells

Godoy, Paulo R. D. V.; Donaires, Flávia S.; Montaldi, Ana Paula; Sakamoto-Hojo, Elza T.

doi:10.1159/000516997

Cited by 5 publications

(4 citation statements)

References 62 publications

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“…Notably, knockdowns in 38 of 67 master regulators altered the proliferation of at least one PD-GSC (p= 1.4e-4) in a genome-wide CRISPR-Cas9 screen on 10 PD-GSCs 31 . In addition, 32 of the 67 master regulators (p = 5.4e-9) have important functions in GBM, such as in GSC self-renewal and maintenance (e.g., SOX2 and SOX9 40,41 and MYC 42 , and repression of GBM cell differentiation (e.g., E2F1 43 , based on disease-to-gene associations in DisGeNET 33 . Despite extensive combinatorial control, including the influence of TFs that were uniquely associated as master regulators of some states, there was some concordance between type of influence (activator or repressor) of some master regulators on states with respect to their disease risk association.…”

Section: Resultsmentioning

confidence: 99%

An atlas of causal and mechanistic drivers of interpatient heterogeneity in glioma

Turkarslan,

He,

Hothi

et al. 2024

Preprint

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Grade IV glioma, formerly known as glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor, and its treatment remains challenging in part due to extensive interpatient heterogeneity in disease driving mechanisms and lack of prognostic and predictive biomarkers. Using mechanistic inference of node-edge relationship (MINER), we have analyzed multiomics profiles from 516 patients and constructed an atlas of causal and mechanistic drivers of interpatient heterogeneity in GBM (gbmMINER). The atlas has delineated how 30 driver mutations act in a combinatorial scheme to causally influence a network of regulators (306 transcription factors and 73 miRNAs) of 179 transcriptional "programs", influencing disease progression in patients across 23 disease states. Through extensive testing on independent patient cohorts, we share evidence that a machine learning model trained on activity profiles of programs within gbmMINER significantly augments risk stratification, identifying patients who are super-responders to standard of care and those that would benefit from 2nd line treatments. In addition to providing mechanistic hypotheses regarding disease prognosis, the activity of programs containing targets of 2nd line treatments accurately predicted efficacy of 28 drugs in killing glioma stem-like cells from 43 patients. Our findings demonstrate that interpatient heterogeneity manifests from differential activities of transcriptional programs, providing actionable strategies for mechanistically characterizing GBM from a systems perspective and developing better prognostic and predictive biomarkers for personalized medicine.

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Section: Resultsmentioning

confidence: 99%

An atlas of causal and mechanistic drivers of interpatient heterogeneity in glioma

Turkarslan,

He,

Hothi

et al. 2024

Preprint

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Section: Discussionmentioning

confidence: 99%

“…CDK and MDM2 inhibitors were also prevalent in laboratory studies testing existing therapies [150,156,160,161,165,176]. Two CDKs were identified as novel molecular targets-namely CDK 5 and 10-and other novel targets include other apoptosis regulators such as E2F1, trichothiodystrophy group A protein (TTDA), and protease activated receptor 2 (PAR2) [267,269,274,279,280] Anti-angiogenic therapies aim to compensate for the robust vascularity of gliomas, particularly GBM [354]. Specifically, vascular endothelial growth factor (VEGF) is overexpressed in GBM, providing rationale for the thirteen published clinical trials investigating VEGF inhibitors.…”

Section: Cell Cycle/apoptosis Pathwaysmentioning

confidence: 99%

Systematic Review of Molecular Targeted Therapies for Adult-Type Diffuse Glioma: An Analysis of Clinical and Laboratory Studies

Muzyka,

Goff,

Choudhary

et al. 2023

IJMS

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Gliomas are the most common brain tumor in adults, and molecularly targeted therapies to treat gliomas are becoming a frequent topic of investigation. The current state of molecular targeted therapy research for adult-type diffuse gliomas has yet to be characterized, particularly following the 2021 WHO guideline changes for classifying gliomas using molecular subtypes. This systematic review sought to characterize the current state of molecular target therapy research for adult-type diffuse glioma to better inform scientific progress and guide next steps in this field of study. A systematic review was conducted in accordance with PRISMA guidelines. Studies meeting inclusion criteria were queried for study design, subject (patients, human cell lines, mice, etc.), type of tumor studied, molecular target, respective molecular pathway, and details pertaining to the molecular targeted therapy—namely the modality, dose, and duration of treatment. A total of 350 studies met the inclusion criteria. A total of 52 of these were clinical studies, 190 were laboratory studies investigating existing molecular therapies, and 108 were laboratory studies investigating new molecular targets. Further, a total of 119 ongoing clinical trials are also underway, per a detailed query on clinicaltrials.gov. GBM was the predominant tumor studied in both ongoing and published clinical studies as well as in laboratory analyses. A few studies mentioned IDH-mutant astrocytomas or oligodendrogliomas. The most common molecular targets in published clinical studies and clinical trials were protein kinase pathways, followed by microenvironmental targets, immunotherapy, and cell cycle/apoptosis pathways. The most common molecular targets in laboratory studies were also protein kinase pathways; however, cell cycle/apoptosis pathways were the next most frequent target, followed by microenvironmental targets, then immunotherapy pathways, with the wnt/β-catenin pathway arising in the cohort of novel targets. In this systematic review, we examined the current evidence on molecular targeted therapy for adult-type diffuse glioma and discussed its implications for clinical practice and future research. Ultimately, published research falls broadly into three categories—clinical studies, laboratory testing of existing therapies, and laboratory identification of novel targets—and heavily centers on GBM rather than IDH-mutant astrocytoma or oligodendroglioma. Ongoing clinical trials are numerous in this area of research as well and follow a similar pattern in tumor type and targeted pathways as published clinical studies. The most common molecular targets in all study types were protein kinase pathways. Microenvironmental targets were more numerous in clinical studies, whereas cell cycle/apoptosis were more numerous in laboratory studies. Immunotherapy pathways are on the rise in all study types, and the wnt/β-catenin pathway is increasingly identified as a novel target.

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“…e2F transcription factor 1 (e2F1) belongs to the e2F family of transcription factors, participating in cellular differentiation and tissue development to maintain body metabolism and homeostasis as a metabolic regulator (11). an number of studies have highlighted the crucial role of e2F1 in various types of malignancies (12), including ovarian cancer (13), prostate cancer (14) and glioblastoma (15). it is noteworthy that the importance of e2F1 in NPC inflammation and tumorigenesis has also been identified in previously published studies (16,17).…”

Section: Cdc25a Inhibition Suppresses Cell Proliferation and Induces ...mentioning

confidence: 99%

CDC25A inhibition suppresses cell proliferation and induces G₁/S‑phase cell cycle arrest in nasopharyngeal carcinoma

Wang

Gong²,

Chen

2023

Mol Med Rep

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nasopharyngeal carcinoma (nPc) is a primary malignancy that originates from the nasopharyngeal region. it has been demonstrated that a decrease in the expression level of cell division cycle gene 25a (cdc25a) suppresses cell viability and induces apoptosis in a variety of different types of cancer. However, at present, the role of cdc25a in nPc has yet to be fully elucidated. Therefore, the aim of the present study was to investigate the role of cdc25a in nPc progression and to explore the potential underlying mechanism. reverse transcription-quantitative Pcr was performed to detect the relative mrna levels of cdc25a and e2F transcription factor 1 (e2F1). Western blot analysis was subsequently used to determine the expression levels of cdc25a, Ki67, proliferating cell nuclear antigen (Pcna) and e2F1. CCK8 assay was employed to measure cell viability and flow cytometric analysis was employed to analyze the cell cycle. The binding sites between the cdc25a promoter and e2F1 were predicted using bioinformatics tools. Finally, luciferase reporter gene and chromatin immunoprecipitation assays were performed to verify the interaction between cdc25a and e2F1. The results obtained suggested that cdc25a is highly expressed in nPc cell lines and cdc25a silencing was found to inhibit cell proliferation, reduce the protein expression levels of Ki67 and Pcna and induce G 1 arrest of nPc cells. Furthermore, e2F1 could bind cdc25a and positively regulate its expression at the transcriptional level. in addition, cdc25a silencing abolished the effects of e2F1 overexpression on cell proliferation and the cell cycle in nPc. Taken together, the findings of the present study showed that cdc25a silencing attenuated cell proliferation and induced cell cycle arrest in nPc and cdc25a was regulated by e2F1. Hence, cdc25a may be a promising therapeutic target for treatment of nPc.

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Anti-Proliferative Effects of E2F1 Suppression in Glioblastoma Cells

Cited by 5 publications

References 62 publications

An atlas of causal and mechanistic drivers of interpatient heterogeneity in glioma

An atlas of causal and mechanistic drivers of interpatient heterogeneity in glioma

Systematic Review of Molecular Targeted Therapies for Adult-Type Diffuse Glioma: An Analysis of Clinical and Laboratory Studies

CDC25A inhibition suppresses cell proliferation and induces G₁/S‑phase cell cycle arrest in nasopharyngeal carcinoma

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Anti-Proliferative Effects of E2F1 Suppression in Glioblastoma Cells

Cited by 5 publications

References 62 publications

An atlas of causal and mechanistic drivers of interpatient heterogeneity in glioma

An atlas of causal and mechanistic drivers of interpatient heterogeneity in glioma

Systematic Review of Molecular Targeted Therapies for Adult-Type Diffuse Glioma: An Analysis of Clinical and Laboratory Studies

CDC25A inhibition suppresses cell proliferation and induces G1/S‑phase cell cycle arrest in nasopharyngeal carcinoma

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CDC25A inhibition suppresses cell proliferation and induces G₁/S‑phase cell cycle arrest in nasopharyngeal carcinoma