E2F1

Gene Summary

Gene:E2F1; E2F transcription factor 1
Aliases: RBP3, E2F-1, RBAP1, RBBP3
Location:20q11.22
Summary:The protein encoded by this gene is a member of the E2F family of transcription factors. The E2F family plays a crucial role in the control of cell cycle and action of tumor suppressor proteins and is also a target of the transforming proteins of small DNA tumor viruses. The E2F proteins contain several evolutionally conserved domains found in most members of the family. These domains include a DNA binding domain, a dimerization domain which determines interaction with the differentiation regulated transcription factor proteins (DP), a transactivation domain enriched in acidic amino acids, and a tumor suppressor protein association domain which is embedded within the transactivation domain. This protein and another 2 members, E2F2 and E2F3, have an additional cyclin binding domain. This protein binds preferentially to retinoblastoma protein pRB in a cell-cycle dependent manner. It can mediate both cell proliferation and p53-dependent/independent apoptosis. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcription factor E2F1
Source:NCBIAccessed: 12 March, 2017

Ontology:

What does this gene/protein do?
Show (33)
Pathways:What pathways are this gene/protein implicaed in?
Show (10)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 12 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 12 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: E2F1 (cancer-related)

Ohtsuka M, Ling H, Ivan C, et al.
H19 Noncoding RNA, an Independent Prognostic Factor, Regulates Essential Rb-E2F and CDK8-β-Catenin Signaling in Colorectal Cancer.
EBioMedicine. 2016; 13:113-124 [PubMed] Free Access to Full Article Related Publications
The clinical significance of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC) remains largely unexplored. Here, we analyzed a large panel of lncRNA candidates with The Cancer Genome Atlas (TCGA) CRC dataset, and identified H19 as the most significant lncRNA associated with CRC patient survival. We further validated such association in two independent CRC cohorts. H19 silencing blocked G1-S transition, reduced cell proliferation, and inhibited cell migration. We profiled gene expression changes to gain mechanism insight of H19 function. Transcriptome data analysis revealed not only previously identified mechanisms such as Let-7 regulation by H19, but also RB1-E2F1 function and β-catenin activity as essential upstream regulators mediating H19 function. Our experimental data showed that H19 affects phosphorylation of RB1 protein by regulating gene expression of CDK4 and CCND1. We further demonstrated that reduced CDK8 expression underlies changes of β-catenin activity, and identified that H19 interacts with macroH2A, an essential regulator of CDK8 gene transcription. However, the relevance of H19-macroH2A interaction in CDK8 regulation remains to be experimentally determined. We further explored the clinical relevance of above mechanisms in clinical samples, and showed that combined analysis of H19 with its targets improved prognostic value of H19 in CRC.

Song C, Lu P, Shi W, et al.
MiR-622 functions as a tumor suppressor and directly targets E2F1 in human esophageal squamous cell carcinoma.
Biomed Pharmacother. 2016; 83:843-849 [PubMed] Related Publications
PURPOSE: MicroRNA-622 has been proven down-regulated in many human malignancies and correlated with tumor progression. However, its role in esophageal squamous cell carcinoma (ESCC) is still unclear. The aim of this study was to explore the expression and function of miR-622 in ESCC.
METHODS: Using quantitative RT-PCR, we detected miR-622 expression in ESCC cell lines and primary tumor tissues. The association of miR-622 expression with clinicopathological factors and prognosis was also analyzed. Then, the effects of miR-622 on the biological behavior of ESCC cells were investigated. At last, the potential regulatory function of miR-622 on E2F1 expression was confirmed.
RESULTS: miR-622 was found to be down-regulated in ESCC tissues and cell lines. Decreased miR-622 expression was closely correlated with aggressive clinicopathological features and poor overall survival. Multivariate regression analysis corroborated that low level of miR-622 expression was an independent unfavourable prognostic factor for patients with ESCC. Up-regulation of miR-622 could significantly reduce ESCC cell proliferation, enhance cell apoptosis, and impair cell invasion and migration in vitro, while down-regulation of miR-622 showed opposite effects. Further, E2F1 was confirmed as a direct target of miR-622 by using Luciferase Reporter Assay.
CONCLUSIONS: These findings indicate that miR-622 may act as a tumor suppressor in ESCC and would serve as a potential therapy target for this disease.

Gao Z, Shi R, Yuan K, Wang Y
Expression and prognostic value of E2F activators in NSCLC and subtypes: a research based on bioinformatics analysis.
Tumour Biol. 2016; 37(11):14979-14987 [PubMed] Related Publications
E2F activators (E2F1-3) codify a family of transcription factors (TFs) in higher eukaryotes. E2F activators are involved in the cell cycle regulation and synthesis of DNA in mammalian cells, and their overexpression has been detected in many human cancers. However, their clinical significance has not been deeply researched in non-small-cell lung cancer (NSCLC), and bioinformatics analysis has never been reported to explore their clinical role in NSCLC. In the current study, we investigated the expression and prognostic value of E2F activators in NSCLC patients through the "TCGA datasets" and the "Kaplan-Meier plotter" (KM plotter) database. Hazard ratio (HR), 95 % confidence intervals, and log-rank P were calculated. Compared with normal tissue samples, E2F activators were overexpressed in NSCLC tissues, in lung adenocarcinoma (LUAD) tissues, and in lung squamous cell carcinoma (LUSC) tissues. In NSCLC patients, E2F1 expression was significantly correlated with age, sex, and tumor stage. E2F2 expression was found to be significantly correlated with sex and tumor size. We further demonstrated that E2F1 and E2F2 overexpressions were significantly associated with poor prognosis. In LUAD patients, E2F1 expression was significantly correlated with tumor size and tumor stage. E2F2 expression was significantly correlated with lymph node status and tumor stage. E2F1 and E2F2 overexpression showed a significant association with poor prognosis, while E2F3 overexpression was significantly correlated to better prognosis. In LUSC patients, E2F1 was concluded to be significantly correlated with tumor stage. However, E2F activators were not found to be correlated to prognosis.

Li Y, Min W, Li M, et al.
Identification of hub genes and regulatory factors of glioblastoma multiforme subgroups by RNA-seq data analysis.
Int J Mol Med. 2016; 38(4):1170-8 [PubMed] Free Access to Full Article Related Publications
Glioblastoma multiforme (GBM) is the most common malignant brain tumor. This study aimed to identify the hub genes and regulatory factors of GBM subgroups by RNA sequencing (RNA-seq) data analysis, in order to explore the possible mechanisms responsbile for the progression of GBM. The dataset RNASeqV2 was downloaded by TCGA-Assembler, containing 169 GBM and 5 normal samples. Gene expression was calculated by the reads per kilobase per million reads measurement, and nor malized with tag count comparison. Following subgroup classification by the non-negative matrix factorization, the differentially expressed genes (DEGs) were screened in 4 GBM subgroups using the method of significance analysis of microarrays. Functional enrichment analysis was performed by DAVID, and the protein-protein interaction (PPI) network was constructed based on the HPRD database. The subgroup-related microRNAs (miRNAs or miRs), transcription factors (TFs) and small molecule drugs were predicted with pre-defined criteria. A cohort of 19,515 DEGs between the GBM and control samples was screened, which were predominantly enriched in cell cycle- and immunoreaction-related pathways. In the PPI network, lymphocyte cytosolic protein 2 (LCP2), breast cancer 1 (BRCA1), specificity protein 1 (Sp1) and chromodomain-helicase-DNA-binding protein 3 (CHD3) were the hub nodes in subgroups 1-4, respectively. Paired box 5 (PAX5), adipocyte protein 2 (aP2), E2F transcription factor 1 (E2F1) and cAMP-response element-binding protein-1 (CREB1) were the specific TFs in subgroups 1-4, respectively. miR‑147b, miR‑770-5p, miR‑220a and miR‑1247 were the particular miRNAs in subgroups 1-4, respectively. Natalizumab was the predicted small molecule drug in subgroup 2. In conclusion, the molecular regulatory mechanisms of GBM pathogenesis were distinct in the different subgroups. Several crucial genes, TFs, miRNAs and small molecules in the different GBM subgroups were identified, which may be used as potential markers. However, further experimental validations may be required.

Wu Y, Yu DD, Hu Y, et al.
Genome-wide profiling of long non-coding RNA expression patterns in the EGFR-TKI resistance of lung adenocarcinoma by microarray.
Oncol Rep. 2016; 35(6):3371-86 [PubMed] Related Publications
Mutations in the epidermal growth factor receptor (EGFR) make lung adenocarcinoma cells sensitive to EGFR tyrosine kinase inhibitors (TKIs). Long-term cancer therapy may cause the occurrence of acquired resistance to EGFR TKIs. Long non-coding RNAs (lncRNAs) play important roles in tumor formation, tumor metastasis and the development of EGFR-TKI resistance in lung cancer. To gain insight into the molecular mechanisms of EGFR-TKI resistance, we generated an EGFR-TKI-resistant HCC827-8-1 cell line and analyzed expression patterns by lncRNA microarray and compared it with its parental HCC827 cell line. A total of 1,476 lncRNA transcripts and 1,026 mRNA transcripts were dysregulated in the HCC827‑8-1 cells. The expression levels of 7 chosen lncRNAs were validated by real-time quantitative PCR. As indicated by functional analysis, several groups of lncRNAs may be involved in the bio-pathways associated with EGFR-TKI resistance through their cis- and/or trans‑regulation of protein-coding genes. Thus, lncRNAs may be used as novel candidate biomarkers and potential targets in EGFR-TKI therapy in the future.

Mori K, Uchida T, Fukumura M, et al.
Linkage of E2F1 transcriptional network and cell proliferation with respiratory chain activity in breast cancer cells.
Cancer Sci. 2016; 107(7):963-71 [PubMed] Free Access to Full Article Related Publications
Mitochondria are multifunctional organelles; they have been implicated in various aspects of tumorigenesis. In this study, we investigated a novel role of the basal electron transport chain (ETC) activity in cell proliferation by inhibiting mitochondrial replication and transcription (mtR/T) using pharmacological and genetic interventions, which depleted mitochondrial DNA/RNA, thereby inducing ETC deficiency. Interestingly, mtR/T inhibition did not decrease ATP levels despite deficiency in ETC activity in different cell types, including MDA-MB-231 breast cancer cells, but it severely impeded cell cycle progression, specifically progression during G2 and/or M phases in the cancer cells. Under these conditions, the expression of a group of cell cycle regulators was downregulated without affecting the growth signaling pathway. Further analysis suggested that the transcriptional network organized by E2F1 was significantly affected because of the downregulation of E2F1 in response to ETC deficiency, which eventually resulted in the suppression of cell proliferation. Thus, in this study, the E2F1-mediated ETC-dependent mechanism has emerged as the regulatory mechanism of cell cycle progression. In addition to E2F1, FOXM1 and BMYB were also downregulated, which contributed specifically to the defects in G2 and/or M phase progression. Thus, ETC-deficient cancer cells lost their growing ability, including their tumorigenic potential in vivo. ETC deficiency abolished the production of reactive oxygen species (ROS) from the mitochondria and a mitochondria-targeted antioxidant mimicked the deficiency, thereby suggesting that ETC activity signaled through ROS production. In conclusion, this novel coupling between ETC activity and cell cycle progression may be an important mechanism for coordinating cell proliferation and metabolism.

Wang Q, Ao Y, Yang K, et al.
Circadian clock gene Per2 plays an important role in cell proliferation, apoptosis and cell cycle progression in human oral squamous cell carcinoma.
Oncol Rep. 2016; 35(6):3387-94 [PubMed] Related Publications
Previous studies have shown that the aberrant expression of period circadian clock 2 (Per2) is closely related to the occurrence and development of cancers, but the specific mechanism remains unclear. In the present study, we used shRNA to downregulate Per2 in oral squamous cell carcinoma (OSCC) Tca8113 cells, and then detected the alterations in cell cycle, cell proliferation and apoptosis by flow cytometric analysis and mRNA expression alterations in all the important genes in the cyclin/cyclin-dependent protein kinase (CDK)/cyclin-dependent kinase inhibitor (CKI) cell cycle network by RT-qPCR. We found that in the Tca8113 cells, after Per2 downregulation, the mRNA expression levels of cyclin A2, B1 and D1, CDK4, CDK6 and E2F1 were significantly increased (P<0.05), the mRNA expression levels of p53, p16 and p21 were significantly decreased (P<0.05), cell proliferation was significantly higher (P<0.05), apoptosis was significantly lower (P<0.05) and the number of cells in the G1/G0 phase was significantly decreased (P<0.05). The present study proves that in OSCC, clock gene Per2 plays an important role in cell cycle progression and the balance of cell proliferation and apoptosis by regulation of the cyclin/CDK/CKI cell cycle network. Further research on Per2 may provide a new effective molecular target for cancer treatments.

Hui L, Wu H, Yang N, et al.
Identification of prognostic microRNA candidates for head and neck squamous cell carcinoma.
Oncol Rep. 2016; 35(6):3321-30 [PubMed] Related Publications
The aim of the present study was to uncover potential prognostic microRNA (miRNA) markers in head and neck squamous cell carcinoma (HNSCC). miRNA expression profile and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. Survival analysis was conducted by Kaplan-Meier method. Then, candidate prognostic miRNAs were screened via Cox proportional hazards regression analysis. Furthermore, target genes of miRNAs were predicted, and their interactions and functions were then analyzed. A total of 15 miRNAs were discovered to be significantly related to overall survival. Among them, miR-1251, miR-618 and miR-328 with p<0.05 were potentially significant prognostic factors of HNSCC. In the protein-protein interaction (PPI) network, the target gene of miR-328, MAX, interacted with multiple genes. The target gene of miR-618, E2F1, interacted with genes such as MAX, SMAD3 and IGF1. Furthermore, the target genes of miR-618 (e.g. E2F1 and SMAD3), and the target genes of miR-328 (e.g. MAX) were significantly enriched in the functions of transcriptional regulation. The target gene of miR-1251, IGF1, was associated with functions such as signal transduction. The above miRNAs (miR-1251, miR-618 and miR-328) may be potential prognostic markers in HNSCC.

Liu Z, Cheng C, Luo X, et al.
CDK4 and miR-15a comprise an abnormal automodulatory feedback loop stimulating the pathogenesis and inducing chemotherapy resistance in nasopharyngeal carcinoma.
BMC Cancer. 2016; 16:238 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In previous investigation, we reported that stably knocking down cyclin-dependent kinase 4(CDK4) induced expression of let-7c, which further suppressed cell cycle transition and cell growth by modulating cell cycle signaling in nasopharyngeal carcinoma (NPC). In this study, we further explored the molecular function and mechanism of CDK4 modulating miRNAs to stimulate cell cycle transition, cell growth, and Cisplatin (DDP) -resistance on in NPC.
METHODS: We identified changes in miRNAs by miRNA array and real-time PCR and the effect on DDP after knocking down CDK4 in NPC cells. Further, we investigated the molecular mechanisms by which CDK4 modulated miR-15a in NPC. Moreover, we also explored the role of miR-15a and the effect on DDP in NPC. Finally, we analyzed the correlation of miR-15a and CDK4 expression in NPC tissues.
RESULTS: In addition to let-7 family members, we observed that upregulated expression of miR-15a was significantly induced in CDK4-suppressed NPC cells. Further, we found that knocking down CDK4 suppressed c-Myc expression, and the latter directly suppressed the expression of miR-15a in NPC. Furthermore, miR-15a as a tumor suppressor antagonized CDK4 repressing cell cycle progression and cell growth in vitro and in vivo and induced the sensitivity of cells to DDP by regulating the c-Myc/CCND1/CDK4/E2F1 pathway in NPC. Finally, miR-15a was negatively weak correlated with the expression of CDK4 in NPC.
CONCLUSIONS: Our studies demonstrate that CDK4 and miR-15a comprise an abnormal automodulatory feedback loop stimulating the pathogenesis and inducing chemotherapy resistance in NPC.

Ochnik AM, Peterson MS, Avdulov SV, et al.
Amplified in Breast Cancer Regulates Transcription and Translation in Breast Cancer Cells.
Neoplasia. 2016; 18(2):100-10 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Control of mRNA translation is fundamentally altered in cancer. Insulin-like growth factor-I (IGF-I) signaling regulates key translation mediators to modulate protein synthesis (e.g. eIF4E, 4E-BP1, mTOR, and S6K1). Importantly the Amplified in Breast Cancer (AIB1) oncogene regulates transcription and is also a downstream mediator of IGF-I signaling.
MATERIALS AND METHODS: To determine if AIB1 also affects mRNA translation, we conducted gain and loss of AIB1 function experiments in estrogen receptor alpha (ERα)(+) (MCF-7L) and ERα(-) (MDA-MB-231, MDA-MB-435 and LCC6) breast cancer cells.
RESULTS: AIB1 positively regulated IGF-I-induced mRNA translation in both ERα(+) and ERα(-) cells. Formation of the eIF4E-4E-BP1 translational complex was altered in the AIB1 ERα(+) and ERα(-) knockdown cells, leading to a reduction in the eIF4E/4E-BP1 and eIF4G/4E-BP1 ratios. In basal and IGF-I stimulated MCF-7 and LCC6 cells, knockdown of AIB1 decreased the integrity of the cap-binding complex, reduced global IGF-I stimulated polyribosomal mRNA recruitment with a concomitant decrease in ten of the thirteen genes tested in polysome-bound mRNAs mapping to proliferation, cell cycle, survival, transcription, translation and ribosome biogenesis ontologies. Specifically, knockdown of AIB1 decreased ribosome-bound mRNA and steady-state protein levels of the transcription factors ERα and E2F1 in addition to reduced ribosome-bound mRNA of the ribosome biogenesis factor BYSL in a cell-line specific manner to regulate mRNA translation.
CONCLUSION: The oncogenic transcription factor AIB1 has a novel role in the regulation of polyribosome recruitment and formation of the translational complex. Combinatorial therapies targeting IGF signaling and mRNA translation in AIB1 expressing breast cancers may have clinical benefit and warrants further investigation.

Kumar A, Coleman I, Morrissey C, et al.
Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer.
Nat Med. 2016; 22(4):369-78 [PubMed] Free Access to Full Article Related Publications
Tumor heterogeneity may reduce the efficacy of molecularly guided systemic therapy for cancers that have metastasized. To determine whether the genomic alterations in a single metastasis provide a reasonable assessment of the major oncogenic drivers of other dispersed metastases in an individual, we analyzed multiple tumors from men with disseminated prostate cancer through whole-exome sequencing, array comparative genomic hybridization (CGH) and RNA transcript profiling, and we compared the genomic diversity within and between individuals. In contrast to the substantial heterogeneity between men, there was limited diversity among metastases within an individual. The number of somatic mutations, the burden of genomic copy number alterations and aberrations in known oncogenic drivers were all highly concordant, as were metrics of androgen receptor (AR) activity and cell cycle activity. AR activity was inversely associated with cell proliferation, whereas the expression of Fanconi anemia (FA)-complex genes was correlated with elevated cell cycle progression, expression of the E2F transcription factor 1 (E2F1) and loss of retinoblastoma 1 (RB1). Men with somatic aberrations in FA-complex genes or in ATM serine/threonine kinase (ATM) exhibited significantly longer treatment-response durations to carboplatin than did men without defects in genes encoding DNA-repair proteins. Collectively, these data indicate that although exceptions exist, evaluating a single metastasis provides a reasonable assessment of the major oncogenic driver alterations that are present in disseminated tumors within an individual, and thus may be useful for selecting treatments on the basis of predicted molecular vulnerabilities.

Liang YX, Lu JM, Mo RJ, et al.
E2F1 promotes tumor cell invasion and migration through regulating CD147 in prostate cancer.
Int J Oncol. 2016; 48(4):1650-8 [PubMed] Related Publications
Increased expression of E2F1 has been reported to be associated with tumor growth and cell survival of prostate cancer (PCa). However, its roles and mechanisms on PCa have not been fully elucidated. The present study found that E2F1 overexpression in PCa tissues was significantly associated with high Gleason score (P=0.01) and advanced pathological stage (P=0.02). In addition, PCa patients with high E2F1 expression more frequently had shorter biochemical recurrence-free survival (P=0.047) than those with low E2F1 expression. Then, we confirmed that the knock-down of E2F1 expression was able to inhibit cell cycle progression, invasion and migration of PCa cell lines in vitro, along with tumor xenograft growth and epithelial-to-mesenchymal transition (EMT) in vivo. Moreover, we identified CD147 as a novel interaction partner for E2F1 through bio-informatic binding site prediction, combined with chromatin immunoprecipitation-PCR (ChIP-PCR) and western blot analysis. Taken together, our data delineate an as yet unrecognized function of E2F1 as enhancer of tumor invasion and migration of PCa via regulating the expression of CD147 in PCa. Importantly, E2F1 may function as a biomarker that can differentiate patients with biochemical recurrent and non-biochemical recurrent disease following radical prostatectomy, highlighting its potential as a therapeutic target.

Bargiela-Iparraguirre J, Prado-Marchal L, Fernandez-Fuente M, et al.
CHK1 expression in Gastric Cancer is modulated by p53 and RB1/E2F1: implications in chemo/radiotherapy response.
Sci Rep. 2016; 6:21519 [PubMed] Free Access to Full Article Related Publications
Radiation has a limited but relevant role in the adjuvant therapy of gastric cancer (GC) patients. Since Chk1 plays a critical function in cellular response to genotoxic agents, we aimed to analyze the role of Chk1 in GC as a biomarker for radiotherapy resistance. We analyzed Chk1 expression in AGS and MKN45 human GC cell lines by RT-QPCR and WB and in a small cohort of human patient's samples. We demonstrated that Chk1 overexpression specifically increases resistance to radiation in GC cells. Accordingly, abrogation of Chk1 activity with UCN-01 and its expression with shChk1 increased sensitivity to bleomycin and radiation. Furthermore, when we assessed Chk1 expression in human samples, we found a correlation between nuclear Chk1 accumulation and a decrease in progression free survival. Moreover, using a luciferase assay we found that Chk1's expression is controlled by p53 and RB/E2F1 at the transcriptional level. Additionally, we present preliminary data suggesting a posttranscriptional regulation mechanism, involving miR-195 and miR-503, which are inversely correlated with expression of Chk1 in radioresistant cells. In conclusion, Chk1/microRNA axis is involved in resistance to radiation in GC, and suggests Chk1 as a potential tool for optimal stratification of patients susceptible to receive adjuvant radiotherapy after surgery.

Cheng C, Lou S, Andrews EH, et al.
Integrative Genomic Analyses Yield Cell-Cycle Regulatory Programs with Prognostic Value.
Mol Cancer Res. 2016; 14(4):332-43 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
UNLABELLED: Liposarcoma is the second most common form of sarcoma, which has been categorized into four molecular subtypes, which are associated with differential prognosis of patients. However, the transcriptional regulatory programs associated with distinct histologic and molecular subtypes of liposarcoma have not been investigated. This study uses integrative analyses to systematically define the transcriptional regulatory programs associated with liposarcoma. Likewise, computational methods are used to identify regulatory programs associated with different liposarcoma subtypes, as well as programs that are predictive of prognosis. Further analysis of curated gene sets was used to identify prognostic gene signatures. The integration of data from a variety of sources, including gene expression profiles, transcription factor-binding data from ChIP-Seq experiments, curated gene sets, and clinical information of patients, indicated discrete regulatory programs (e.g., controlled by E2F1 and E2F4), with significantly different regulatory activity in one or multiple subtypes of liposarcoma with respect to normal adipose tissue. These programs were also shown to be prognostic, wherein liposarcoma patients with higher E2F4 or E2F1 activity associated with unfavorable prognosis. A total of 259 gene sets were significantly associated with patient survival in liposarcoma, among which > 50% are involved in cell cycle and proliferation.
IMPLICATIONS: These integrative analyses provide a general framework that can be applied to investigate the mechanism and predict prognosis of different cancer types.

Rajitha B, Belalcazar A, Nagaraju GP, et al.
Inhibition of NF-κB translocation by curcumin analogs induces G0/G1 arrest and downregulates thymidylate synthase in colorectal cancer.
Cancer Lett. 2016; 373(2):227-33 [PubMed] Related Publications
Cell cycle progression and DNA synthesis are essential steps in cancer cell growth and resistance. Thymidylate synthase (TS) is a therapeutic target for 5FU. Curcumin is a potent inhibitor of NF-κB. EF31 and UBS109 are potent synthetic analogues of curcumin. We tested the hypothesis that inhibition of NF-κB translocation by curcumin and its analogs EF31 and UBS109 can inhibit cell cycle progression and downregulate TS levels in colorectal cancer (CRC) cell lines. Two CRC cell lines (HCT116 and HT-29) were either untreated (control) or treated with IC50 concentrations of curcumin, EF31 UBS109 led to G0/G1 cell cycle arrest. Treatment with curcumin, EF31 or UBS109 inhibited NF-κB, downregulated survival pathways and inhibited cell cycle progression. Arrest in the G0/G1 phase was associated with downregulation of the transcription factor E2F-1 and its target gene TS. NF-κB over-expression induced E2F-1 and TS protein and mRNA levels in both cell lines. EF31 and UBS109 treatment significantly decreased tumor growth in compared to untreated tumors. EF31 and UBS109 are promising agents for the prevention and treatment of CRC.

Nikolai BC, Lanz RB, York B, et al.
HER2 Signaling Drives DNA Anabolism and Proliferation through SRC-3 Phosphorylation and E2F1-Regulated Genes.
Cancer Res. 2016; 76(6):1463-75 [PubMed] Article available free on PMC after 15/03/2017 Related Publications
Approximately 20% of early-stage breast cancers display amplification or overexpression of the ErbB2/HER2 oncogene, conferring poor prognosis and resistance to endocrine therapy. Targeting HER2(+) tumors with trastuzumab or the receptor tyrosine kinase (RTK) inhibitor lapatinib significantly improves survival, yet tumor resistance and progression of metastatic disease still develop over time. Although the mechanisms of cytosolic HER2 signaling are well studied, nuclear signaling components and gene regulatory networks that bestow therapeutic resistance and limitless proliferative potential are incompletely understood. Here, we use biochemical and bioinformatic approaches to identify effectors and targets of HER2 transcriptional signaling in human breast cancer. Phosphorylation and activity of the Steroid Receptor Coactivator-3 (SRC-3) is reduced upon HER2 inhibition, and recruitment of SRC-3 to regulatory elements of endogenous genes is impaired. Transcripts regulated by HER2 signaling are highly enriched with E2F1 binding sites and define a gene signature associated with proliferative breast tumor subtypes, cell-cycle progression, and DNA replication. We show that HER2 signaling promotes breast cancer cell proliferation through regulation of E2F1-driven DNA metabolism and replication genes together with phosphorylation and activity of the transcriptional coactivator SRC-3. Furthermore, our analyses identified a cyclin-dependent kinase (CDK) signaling node that, when targeted using the CDK4/6 inhibitor palbociclib, defines overlap and divergence of adjuvant pharmacologic targeting. Importantly, lapatinib and palbociclib strictly block de novo synthesis of DNA, mostly through disruption of E2F1 and its target genes. These results have implications for rational discovery of pharmacologic combinations in preclinical models of adjuvant treatment and therapeutic resistance.

Jeong S, Lee J, Kim D, et al.
Relationship of Focally Amplified Long Noncoding on Chromosome 1 (FAL1) lncRNA with E2F Transcription Factors in Thyroid Cancer.
Medicine (Baltimore). 2016; 95(4):e2592 [PubMed] Article available free on PMC after 15/03/2017 Related Publications
Recent functional genomic studies revealed that the oncogenic activity of focally amplified lncRNA on chromosome 1 (FAL1, ENSG00000228126) contributes to tumor growth by p21 repression in human cancers. However, the expression of FAL1 was not investigated in papillary thyroid cancer (PTC). We aimed to determine if FAL1 was up-regulated in PTC compared to paired contralateral normal thyroid tissues, and to investigate the potential targets of this lncRNA and its clinicopathological significance in PTC. We analyzed FAL1 and p21 expression levels in 100 PTC samples and matched normal thyroid tissue by qRT-PCR. Using lncRNA microarray data from the Gene Expression Omnibus (accession no. GSE61763), we explored potential targets of FAL1 by Gene Set Enrichment Analysis, followed by verification by qRT-PCR in our PTC samples. A cross-sectional observational study was conducted to investigate the relationship between patients' clinicopathological features and FAL1 expression. FAL1 expression was significantly higher in PTC than in paired normal thyroid tissues (paired t test, P < 0.001). p21 mRNA expression was also increased, not decreased, in PTC, and had no correlation with FAL1 expression (r = 0.0897, P = 0.4002). Gene Set Enrichment Analysis, using publicly available microarray data, indicated that a gene set related to the cell cycle, including E2F transcription factors 1 and 2, and cyclin D1, was coordinately enriched among samples with high FAL1 expression. A volcano plot showed that E2F1, E2F2, and VEGFA mRNAs were increased in the high FAL1 samples. In clinicopathological analyses, multifocality was more frequently observed in PTC patients with high FAL1 (P = 0.018). Multivariate analysis showed that high FAL1 expression increased the risk of multifocality (after adjustment for clinical variables, OR = 4.019, CI = 1.041-11.020, P = 0.043). FAL1 may have a role in cell-cycle progression and may be associated with aggressive tumor behavior in PTC.

Zhang Z, Mao H, Du X, et al.
A novel small molecule agent displays potent anti-myeloma activity by inhibiting the JAK2-STAT3 signaling pathway.
Oncotarget. 2016; 7(8):9296-308 [PubMed] Article available free on PMC after 15/03/2017 Related Publications
The oncogenic STAT3 signaling pathway is emerging as a promising target for the treatment of multiple myeloma (MM). In the present study, we identified a novel STAT3 inhibitor SC99 in a target-based high throughput screen. SC99 inhibited JAK2-STAT3 activation but had no effects on other transcription factors such as NF-κB, and kinases such as AKT, ERK, and c-Src that are in association with STAT3 signaling pathway. Furthermore, SC99 downregulated the expression of STAT3-modulated genes, including Bcl-2, Bcl-xL, VEGF, cyclin D2, and E2F-1. By inhibiting the STAT3 signaling, SC99 induced MM cell apoptosis which could be partly abolished by the ectopic expression of STAT3. Furthermore, SC99 displayed potent anti-MM activity in two independent MM xenograft models in nude mice. Oral administration of SC99 led to marked decrease of tumor growth within 10 days at a daily dosage of 30 mg/kg, but did not raise toxic effects. Taken together, this study identified a novel oral JAK2/STAT3 inhibitor that could be developed as an anti-myeloma agent.

Vera B, Martínez-Vélez N, Xipell E, et al.
Characterization of the Antiglioma Effect of the Oncolytic Adenovirus VCN-01.
PLoS One. 2016; 11(1):e0147211 [PubMed] Article available free on PMC after 15/03/2017 Related Publications
Despite the recent advances in the development of antitumor therapies, the prognosis for patients with malignant gliomas remains dismal. Therapy with tumor-selective viruses is emerging as a treatment option for this devastating disease. In this study we characterize the anti-glioma effect of VCN-01, an improved hyaluronidase-armed pRB-pathway-selective oncolytic adenovirus that has proven safe and effective in the treatment of several solid tumors. VCN-01 displayed a significant cytotoxic effect on glioma cells in vitro. In vivo, in two different orthotopic glioma models, a single intra-tumoral administration of VCN-01 increased overall survival significantly and led to long-term survivors free of disease.

Aguda BD, del Rosario RC, Chan MW
Oncogene-tumor suppressor gene feedback interactions and their control.
Math Biosci Eng. 2015; 12(6):1277-88 [PubMed] Related Publications
We propose the hypothesis that for a particular type of cancer there exists a key pair of oncogene (OCG) and tumor suppressor gene (TSG) that is normally involved in strong stabilizing negative feedback loops (nFBLs) of molecular interactions, and it is these interactions that are sufficiently perturbed during cancer development. These nFBLs are thought to regulate oncogenic positive feedback loops (pFBLs) that are often required for the normal cellular functions of oncogenes. Examples given in this paper are the pairs of MYC and p53, KRAS and INK4A, and E2F1 and miR-17-92. We propose dynamical models of the aforementioned OCG-TSG interactions and derive stability conditions of the steady states in terms of strengths of cycles in the qualitative interaction network. Although these conditions are restricted to predictions of local stability, their simple linear expressions in terms of competing nFBLs and pFBLs make them intuitive and practical guides for experimentalists aiming to discover drug targets and stabilize cancer networks.

Zhan L, Zhang Y, Wang W, et al.
E2F1: a promising regulator in ovarian carcinoma.
Tumour Biol. 2016; 37(3):2823-31 [PubMed] Related Publications
E2F is a family of transcription factors that recognized to regulate the expression of genes essential for a wide range of cellular functions, including cell cycle progression, DNA repair, DNA replication, differentiation, proliferation, and apoptosis. E2F1, the most classic member of the E2F family, exhibits a complex role in tumor development regulation. In recent years, a growing body of data suggested an intimate relationship between E2F1 and ovarian carcinoma. And E2F1 was well identified to play dual functions and serve as a useful prognostic indicator in ovarian carcinoma. However, the mechanism underlying E2F1 associated with ovarian carcinoma remains elusive. It is necessary to clarify the fundamental role of E2F1 in ovarian carcinoma. In this review, we tried to sum up the knowledge of E2F1, including its structure and related mechanism. We also attempt to absorb the research achievements and collect the mechanism of E2F1 in ovarian carcinoma.

Chen CL, Uthaya Kumar DB, Punj V, et al.
NANOG Metabolically Reprograms Tumor-Initiating Stem-like Cells through Tumorigenic Changes in Oxidative Phosphorylation and Fatty Acid Metabolism.
Cell Metab. 2016; 23(1):206-19 [PubMed] Article available free on PMC after 15/03/2017 Related Publications
Stem cell markers, including NANOG, have been implicated in various cancers; however, the functional contribution of NANOG to cancer pathogenesis has remained unclear. Here, we show that NANOG is induced by Toll-like receptor 4 (TLR4) signaling via phosphorylation of E2F1 and that downregulation of Nanog slows down hepatocellular carcinoma (HCC) progression induced by alcohol western diet and hepatitis C virus protein in mice. NANOG ChIP-seq analyses reveal that NANOG regulates the expression of genes involved in mitochondrial metabolic pathways required to maintain tumor-initiating stem-like cells (TICs). NANOG represses mitochondrial oxidative phosphorylation (OXPHOS) genes, as well as ROS generation, and activates fatty acid oxidation (FAO) to support TIC self-renewal and drug resistance. Restoration of OXPHOS activity and inhibition of FAO renders TICs susceptible to a standard care chemotherapy drug for HCC, sorafenib. This study provides insights into the mechanisms of NANOG-mediated generation of TICs, tumorigenesis, and chemoresistance through reprogramming of mitochondrial metabolism.

Ghosh A, Ghosh S, Dasgupta D, et al.
Hepatitis B Virus X Protein Upregulates hELG1/ ATAD5 Expression through E2F1 in Hepatocellular Carcinoma.
Int J Biol Sci. 2016; 12(1):30-41 [PubMed] Article available free on PMC after 15/03/2017 Related Publications
The precise mechanism by which HBx protein of hepatitis B virus (HBV) impacts on hepato-carcinogenesis remain largely elusive despite strong evidences for its' involvement in the process. Here, we have investigated the role of HBx on expression of a novel gene hELG1/ATAD5, which is required for genome maintenance and its' importance in hepatocarcinogenesis. This study has for the first time showed that the expression of this gene was significantly higher in human cancer such as HBV-associated hepatocellular carcinoma (HCC) and in different HCC cell lines compared to normal liver. In addition, a significant elevation in ATAD5 expression was also found in HBx transfected HCC cell lines implicating HBx mediated transcriptional regulation on ATAD5. Using different deletion mutant constructs of putative promoter, the active promoter region was first identified here and subsequently the regulatory region of HBx was mapped by promoter-luciferase assay. But ChIP assay with anti-HBx antibody revealed that HBx was not physically present in ATAD5 transcription machinery whereas anti-E2F1 antibody showed the presence of E2F1 in the complex. Luciferase assay with E2F1 binding site mutant had further confirmed it. Moreover, both loss-and gain-of-function studies of ATAD5 showed that ATAD5 could enhance HBV production in transfected cells whereas knock down of ATAD5 increased the sensitivity of HCC cell line to chemotherapeutics 5-fluorouracil. Overall, this data suggests that a positive feedback loop regulation between ATAD5 and HBV contributed to both viral replication and chemo-resistance of HCC cells.

Yang S, Wu B, Sun H, et al.
Interrupted E2F1-miR-34c-SCF negative feedback loop by hyper-methylation promotes colorectal cancer cell proliferation.
Biosci Rep. 2015; 36(1):e00293 [PubMed] Article available free on PMC after 15/03/2017 Related Publications
Tumour suppressor miR-34c deficiency resulted from hyper-methylation in its promoter is believed to be one of the main causes of colorectal cancer (CRC). Till date, miR-34c has been validated as a direct target of p53; but previous evidence suggested other transcription factor(s) must be involved in miR-34c transcription. In the present study, we in the first place identified a core promoter region (-1118 to -883 bp) of pre-miR-34c which was embedded within a hyper-methylated CpG island. Secondly, E2F1 promoted miR-34c transcription by physical interaction with the miR-34c promoter at site -897 to -889 bp. The transcriptional activating effect of E2F1 on miR-34c was in a p53 independent manner but profoundly promoted in the presence of p53 with exposure to 5-aza-2'-deoxycytidine (DAC). Thirdly, stem cell factor (SCF), a miR-34c target, was specifically reduced upon an introduction of E2F1 which lead to suppression of CRC cell proliferation. The E2F1-suppressed cell proliferation was partially abrogated by additional miR-34c inhibitor, indicating that the anti-proliferation effect of E2F1 was probably through activating miR-34c-SCF axis. Finally, SCF/KIT signalling increased E2F1 production by reducing its proteosomal degradation dependent on PI3K/Akt-GSK3β pathway. In conclusion, our results suggested the existence of E2F1-miR-34c-SCF negative feedback loop which was interrupted by the hyper-methylation of miR-34c promoter in CRC cells and increased cell proliferation.

Karlsson E, Magić I, Bostner J, et al.
Revealing Different Roles of the mTOR-Targets S6K1 and S6K2 in Breast Cancer by Expression Profiling and Structural Analysis.
PLoS One. 2015; 10(12):e0145013 [PubMed] Article available free on PMC after 15/03/2017 Related Publications
BACKGROUND: The AKT/mTORC1/S6K pathway is frequently overstimulated in breast cancer, constituting a promising therapeutic target. The benefit from mTOR inhibitors varies, likely as a consequence of tumour heterogeneity, and upregulation of several compensatory feed-back mechanisms. The mTORC1 downstream effectors S6K1, S6K2, and 4EBP1 are amplified and overexpressed in breast cancer, associated with a poor outcome and divergent endocrine treatment benefit. S6K1 and S6K2 share high sequence homology, but evidence of partly distinct biological functions is emerging. The aim of this work was to explore possible different roles and treatment target potentials of S6K1 and S6K2 in breast cancer.
MATERIALS AND METHODS: Whole-genome expression profiles were compared for breast tumours expressing high levels of S6K1, S6K2 or 4EBP1, using public datasets, as well as after in vitro siRNA downregulation of S6K1 and/or S6K2 in ZR751 breast cancer cells. In silico homology modelling of the S6K2 kinase domain was used to evaluate its possible structural divergences to S6K1.
RESULTS: Genome expression profiles were highly different in S6K1 and S6K2 high tumours, whereas S6K2 and 4EBP1 profiles showed significant overlaps, both correlated to genes involved in cell cycle progression, among these the master regulator E2F1. S6K2 and 4EBP1 were inversely associated with IGF1 levels, and their prognostic value was shown to be restricted to tumours positive for IGFR and/or HER2. In vitro, S6K1 and S6K2 silencing resulted in upregulation of genes in the mTORC1 and mTORC2 complexes. Isoform-specific silencing also showed distinct patterns, e.g. S6K2 downregulation lead to upregulation of several cell cycle associated genes. Structural analyses of the S6K2 kinase domain showed unique structure patterns, deviating from those of S6K1, facilitating the development of isoform-specific inhibitors. Our data support emerging proposals of distinct biological features of S6K1 and S6K2, suggesting their importance as separate oncogenes and clinical markers, where specific targeting in different breast cancer subtypes could facilitate further individualised therapies.

Nie FQ, Ma S, Xie M, et al.
Decreased long noncoding RNA MIR31HG is correlated with poor prognosis and contributes to cell proliferation in gastric cancer.
Tumour Biol. 2016; 37(6):7693-701 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) are emerging as key regulators governing fundamental biological processes, and their disorder expression involves in the development of several human cancers. MIR31HG, an lncRNA located in 9p21.3 and 2166 bp in length, has been found to be upregulated in breast cancer and contributes to cell proliferation and invasion. However, the expression pattern and biological function of MIR31HG in gastric cancer are still not well documented. In this study, we found that MIR31HG expression is decreased in gastric cancer tissues and associated with larger tumor size and advanced pathological stage. Patients with lower MIR31HG expression had a relatively poor prognosis. Furthermore, ectopic over-expression of MIR31HG could inhibit gastric cancer (GC) cell proliferation both in vitro and in vivo, while knockdown of MIR31HG by small interfering RNA (siRNA) promoted cell proliferation in GC cells partly via regulating E2F1 and p21 expression. Our findings present that decreased MIR31HG is involved in GC development and could be identified as a poor prognostic biomarker in GC patients.

Wang T, Mu L, Jin H, et al.
The effects of bufadienolides on HER2 overexpressing breast cancer cells.
Tumour Biol. 2016; 37(6):7155-63 [PubMed] Related Publications
HER2 is a proto-oncogene frequently amplified in human breast cancer, its overexpression is correlated with tamoxifen resistance and decreased recurrence-free survival. Arenobufagin and bufalin are homogeneous bufadienolides of cardiac glycosides agents. In this research, we studied the effects of arenobufagin and bufalin on cellular survival and proliferation of HER2 overexpressing breast cancer cells and the mechanism under the results including the direct effect on HER2 downstream pathways. Our results showed that arenobufagin and bufalin could significantly inhibit the proliferation and survival of HER2 overexpressing breast cancer cells, along with the declination of SRC-1, SRC-3, nuclear transcription factor E2F1, phosphorylated AKT, and ERK. And the combination of each bufadienolide in low dose with tamoxifen could significantly enhance the inhibitory effect of tamoxifen on HER2 overexpressing breast cancer cells. All above suggest that arenobufagin and bufalin may be potential therapy adjuvants for HER2 overexpressing breast cancer therapy.

Xu H, Xu K, He HH, et al.
Integrative Analysis Reveals the Transcriptional Collaboration between EZH2 and E2F1 in the Regulation of Cancer-Related Gene Expression.
Mol Cancer Res. 2016; 14(2):163-72 [PubMed] Article available free on PMC after 15/03/2017 Related Publications
UNLABELLED: Overexpression of EZH2 is frequently linked to the advanced and metastatic stage of cancers. The mechanisms of its oncogenic function can be context specific, and may vary depending on the protein complexes that EZH2 interacts with. To identify novel transcriptional collaborators of EZH2 in cancers, a computational approach was developed that integrates protein-DNA binding data, cell perturbation gene expression data, and compendiums of tumor expression profiles. This holistic approach identified E2F1, a known mediator of the Rb tumor suppressor, as a transcriptional collaborator of EZH2 in castration-resistant prostate cancer. Subsequent analysis and experimental validation found EZH2 and E2F1 cobind to a subset of chromatin sites lacking H3K27 trimethylation, and activate genes that are critical for prostate cancer progression. The collaboration of EZH2 and E2F1 in transcriptional regulation is also observed in diffuse large B-cell lymphoma cell lines, where activation of the transcriptional network is concordant with the cellular response to the EZH2 inhibitor.
IMPLICATIONS: The direct collaboration between EZH2 and Rb/E2F1 pathway provides an innovative mechanism underlying the cascade of tumor progression, and lays the foundation for the development of new anticancer targets/strategies.

Lin Z, Ren N, Jiang Y, et al.
Adenovirus-Mediated E2F-1 Gene Transfer Augments Gemcitabine-Induced Apoptosis in Human Colon Cancer Cells.
Clin Lab. 2015; 61(10):1435-44 [PubMed] Related Publications
BACKGROUND: E2F-1 is a transcription factor that stimulates cellular proliferation and cell cycle progression. E2F-1 alone is sufficient to stimulate cells to initiate DNA synthesis, and this unscheduled entry into S phase is a potent trigger of apoptosis. Gemcitabine, a novel pyrimidine analogue with structural and metabolic similarities to cytarabine, also can efficiently induce apoptosis, especially for cancer cells that are already in S phase. Gemcitabine has established antitumor activity against solid tumors, including head and neck, ovarian, and non-small cell lung cancers. Therefore, we hypothesized that exogenous E2F-1 expression could accumulate cells in the S phase and thus sensitize them to gemcitabine.
METHODS: We constructed an adenoviral vector (AdCMVE2F-1) to transduce the exogenous E2F-1 gene into human cancer cells. Infection of human colon cancer cells with AdCMVE2F-1 resulted in the overexpression of E2F-1 mRNA and protein in a dose-dependent manner and consequently induced accumulation in S phase as measured by FACS analysis. To assess the synergistic antitumor effect of AdCMVE2F-1 and gemcitabine, the human colon cancer cel lines SW620, DLD-1, and LoVo were infected with AdCMVE2F-1 at various multiplicities of infection and then exposed to various concentrations of gemcitabine 24 hours after infection.
RESULT: Isobologram analysis showed that E2F-1-transduced cancer cells exhibited higher sensitivity to gemcitabine treatment compared to control virus-infected cells. Treatment with AdCMVE2F-1 plus gemcitabine enhanced endogenous p53 expression in LoVo cells, which contain wild-type p53; however, the finding that the synergistic effect can also be observed in mutant p53-expressing SW620 and DLD-1 cells suggests that wild-type p53 function may not be necessary for the therapeutic effects of this drug combination. Conclusions: Our data demonstrate that overexpression of ectopic E2F-1 protein may render cels more sensitive to gemcitabine-mediated apoptosis, an outcome that has important general implications for the treatment of human cancer.

Tarangelo A, Lo N, Teng R, et al.
Recruitment of Pontin/Reptin by E2f1 amplifies E2f transcriptional response during cancer progression.
Nat Commun. 2015; 6:10028 [PubMed] Article available free on PMC after 15/03/2017 Related Publications
Changes in gene expression during tumorigenesis are often considered the consequence of de novo mutations occurring in the tumour. An alternative possibility is that the transcriptional response of oncogenic transcription factors evolves during tumorigenesis. Here we show that aberrant E2f activity, following inactivation of the Rb gene family in a mouse model of liver cancer, initially activates a robust gene expression programme associated with the cell cycle. Slowly accumulating E2f1 progressively recruits a Pontin/Reptin complex to open the chromatin conformation at E2f target genes and amplifies the E2f transcriptional response. This mechanism enhances the E2f-mediated transactivation of cell cycle genes and initiates the activation of low binding affinity E2f target genes that regulate non-cell-cycle functions, such as the Warburg effect. These data indicate that both the physiological and the oncogenic activities of E2f result in distinct transcriptional responses, which could be exploited to target E2f oncogenic activity for therapy.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. E2F1 Transcription Factor, Cancer Genetics Web: http://www.cancer-genetics.org/E2F1.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 12 March, 2017     Cancer Genetics Web, Established 1999