Gene Summary

Gene:E2F4; E2F transcription factor 4
Aliases: E2F-4
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 binds to all three of the tumor suppressor proteins pRB, p107 and p130, but with higher affinity to the last two. It plays an important role in the suppression of proliferation-associated genes, and its gene mutation and increased expression may be associated with human cancer. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcription factor E2F4
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 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.

  • Transcription Factors
  • Colorectal Cancer
  • E2F4 Transcription Factor
  • Gene Expression Profiling
  • Apoptosis
  • Up-Regulation
  • beta Catenin
  • Promoter Regions
  • Polymerase Chain Reaction
  • DNA Repair
  • Repressor Proteins
  • Cell Cycle Proteins
  • Retinoblastoma-Like Protein p130
  • Trinucleotide Repeats
  • Protein Binding
  • Breast Cancer
  • Binding Sites
  • Protein-Serine-Threonine Kinases
  • Immunohistochemistry
  • Neoplasm Proteins
  • Cancer Gene Expression Regulation
  • E2F Transcription Factors
  • Cell Cycle
  • BCL2 protein
  • Receptor, Transforming Growth Factor-beta Type II
  • Proto-Oncogene Proteins
  • E2F1
  • Mutation
  • Nuclear Proteins
  • Messenger RNA
  • Cell Proliferation
  • Prostate Cancer
  • Trans-Activators
  • Carrier Proteins
  • Down-Regulation
  • RB1
  • Proto-Oncogene Proteins c-myc
  • DNA-Binding Proteins
  • Chromosome 16
  • Transforming Growth Factor beta Receptors
  • Microsatellite Repeats
Tag cloud generated 31 August, 2019 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: E2F4 (cancer-related)

Ramezani S, Sharafshah A, Mirzanejad L, Hadavi M
Association of PARP1 rs4653734, rs907187 and rs1136410 variants with breast cancer risk among Iranian women.
Gene. 2019; 712:143954 [PubMed] Related Publications
BACKGROUND: Breast cancer (BC) is the highest cause of mortality among female cancer patients. In some cases, BC is due to Poly [ADP-ribose] polymerase 1 (PARP1) gene dysregulation, which has been involved in various important cellular processes. Among Iranian women, the association between PARP1 polymorphisms and BC was never studied before so in this case-control study, the genetic association of three SNPs (rs1136410, rs907187 and rs4653734) was analyzed with susceptibility to BC.
METHODS: The study subjects were 386 Iranian females divided into 186 patients and 200 healthy controls. The genotypes of PARP1 variants were detected using ARMS and a combined ARMS-RFLP PCR method.
RESULTS: The results showed that Carriers of CG and GG genotypes of the variant rs4653734 were at higher risk of BC compared with wild-type carriers (CC) and this variant was statistically significant under a recessive model of inheritance. Moreover, rs907187 was related to increased BC risk in the CC and GG genotypes under dominant and recessive models of inheritance. The G allele frequency of rs4653734 and rs907187 was higher in breast cancer patients than in normal subjects. No association was detected between rs1136410 and susceptibility to BC among studied groups. Furthermore, A-G-C haplotype was linked to an increased BC risk, whereas A-C-C and A-C-G haplotypes were related to a decreased risk of BC. In Silico predictions suggested that rs907187 affects E2F and E2F-4 transcription factors binding site.
CONCLUSIONS: The current study suggests that rs907187 and rs4653734 have remarkable associations with BC risk among Iranian women.

Rahman MR, Islam T, Gov E, et al.
Identification of Prognostic Biomarker Signatures and Candidate Drugs in Colorectal Cancer: Insights from Systems Biology Analysis.
Medicina (Kaunas). 2019; 55(1) [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is the second most common cause of cancer-related death in the world, but early diagnosis ameliorates the survival of CRC. This report aimed to identify molecular biomarker signatures in CRC. We analyzed two microarray datasets (GSE35279 and GSE21815) from the Gene Expression Omnibus (GEO) to identify mutual differentially expressed genes (DEGs). We integrated DEGs with protein⁻protein interaction and transcriptional/post-transcriptional regulatory networks to identify reporter signaling and regulatory molecules; utilized functional overrepresentation and pathway enrichment analyses to elucidate their roles in biological processes and molecular pathways; performed survival analyses to evaluate their prognostic performance; and applied drug repositioning analyses through Connectivity Map (CMap) and geneXpharma tools to hypothesize possible drug candidates targeting reporter molecules. A total of 727 upregulated and 99 downregulated DEGs were detected. The PI3K/Akt signaling, Wnt signaling, extracellular matrix (ECM) interaction, and cell cycle were identified as significantly enriched pathways. Ten hub proteins (ADNP, CCND1, CD44, CDK4, CEBPB, CENPA, CENPH, CENPN, MYC, and RFC2), 10 transcription factors (ETS1, ESR1, GATA1, GATA2, GATA3, AR, YBX1, FOXP3, E2F4, and PRDM14) and two microRNAs (miRNAs) (miR-193b-3p and miR-615-3p) were detected as reporter molecules. The survival analyses through Kaplan⁻Meier curves indicated remarkable performance of reporter molecules in the estimation of survival probability in CRC patients. In addition, several drug candidates including anti-neoplastic and immunomodulating agents were repositioned. This study presents biomarker signatures at protein and RNA levels with prognostic capability in CRC. We think that the molecular signatures and candidate drugs presented in this study might be useful in future studies indenting the development of accurate diagnostic and/or prognostic biomarker screens and efficient therapeutic strategies in CRC.

Manicum T, Ni F, Ye Y, et al.
Prognostic values of
Biosci Rep. 2018; 38(6) [PubMed] Free Access to Full Article Related Publications
Gastric cancer (GC) is the second most frequent cause of cancer-related mortality in the world, with Eastern Asia having the highest incidence rates. E2F is a family of transcription factor proteins that has a variety of functions, which include control of cell cycle, cell differentiation, DNA damage response and cell death. E2F transcription factors are divided into two subfamilies: transcription activators (E2F transcription factors 1 (E2F1), 2 (E2F2) and 3a (E2F3a)) and repressors (E2F3b, E2F transcription factors 4 (E2F4), 5 (E2F5), 6 (E2F6), 7 (E2F7) and 8 (E2F8)). Studies have demonstrated that E2F had prognostic significance in a number of cancers. However, the entirety of the prognostic roles of

Iness AN, Felthousen J, Ananthapadmanabhan V, et al.
The cell cycle regulatory DREAM complex is disrupted by high expression of oncogenic B-Myb.
Oncogene. 2019; 38(7):1080-1092 [PubMed] Free Access to Full Article Related Publications
Overexpression of the oncogene MYBL2 (B-Myb) is associated with increased cell proliferation and serves as a marker of poor prognosis in cancer. However, the mechanism by which B-Myb alters the cell cycle is not fully understood. In proliferating cells, B-Myb interacts with the MuvB core complex including LIN9, LIN37, LIN52, RBBP4, and LIN54, forming the MMB (Myb-MuvB) complex, and promotes transcription of genes required for mitosis. Alternatively, the MuvB core interacts with Rb-like protein p130 and E2F4-DP1 to form the DREAM complex that mediates global repression of cell cycle genes in G0/G1, including a subset of MMB target genes. Here, we show that overexpression of B-Myb disrupts the DREAM complex in human cells, and this activity depends on the intact MuvB-binding domain in B-Myb. Furthermore, we found that B-Myb regulates the protein expression levels of the MuvB core subunit LIN52, a key adapter for assembly of both the DREAM and MMB complexes, by a mechanism that requires S28 phosphorylation site in LIN52. Given that high expression of B-Myb correlates with global loss of repression of DREAM target genes in breast and ovarian cancer, our findings offer mechanistic insights for aggressiveness of cancers with MYBL2 amplification, and establish the rationale for targeting B-Myb to restore cell cycle control.

Bhawe K, Roy D
Interplay between NRF1, E2F4 and MYC transcription factors regulating common target genes contributes to cancer development and progression.
Cell Oncol (Dordr). 2018; 41(5):465-484 [PubMed] Related Publications
BACKGROUND: Nuclear respiratory factor 1 (NRF1), historically perceived as a protein regulating genes controlling mitochondrial biogenesis, is now widely recognized as a multifunctional protein and as a key player in the transcriptional modulation of genes implicated in various cellular functions. Here, we present emerging data supporting novel roles of NRF1 in cancer development and progression through its interplay with the transcription factors E2F4 and MYC. To identify common human NRF1, E2F4 and MYC target genes, we analyzed the Encyclopedia of DNA Elements (ENCODE) NRF1 ChIP-Seq data. By doing so, we identified 9253 common target genes with NRF1, E2F4 and MYC binding motifs. NRF1 binding motifs were found to be present in genes operating in signaling pathways governing all hallmarks of malignant transformation and progression, including proliferation, invasion, self-renewal and apoptosis.
CONCLUSIONS: In addition to controlling mitochondrial biogenesis NRF1, in conjunction with E2F4 and MYC, may play a critical role in the acquisition of human cancer characteristics. Additionally, NRF1 may orchestrate both MYC and E2F4 to regulate common target genes linked to multiple networks in the development and progression of cancer. A comprehensive understanding of this dynamic interplay will set the stage, not only for the design of novel treatment strategies, but also for the discovery of pan-cellular transcription factor regulatory strategies to predict cancer risk, therapy response and patient prognosis.

Kori M, Yalcin Arga K
Potential biomarkers and therapeutic targets in cervical cancer: Insights from the meta-analysis of transcriptomics data within network biomedicine perspective.
PLoS One. 2018; 13(7):e0200717 [PubMed] Free Access to Full Article Related Publications
The malignant neoplasm of the cervix, cervical cancer, has effects on the reproductive tract. Although infection with oncogenic human papillomavirus is essential for cervical cancer development, it alone is insufficient to explain the development of cervical cancer. Therefore, other risk factors such as host genetic factors should be identified, and their importance in cervical cancer induction should be determined. Although gene expression profiling studies in the last decade have made significant molecular findings about cervical cancer, adequate screening and effective treatment strategies have yet to be achieved. In the current study, meta-analysis was performed on cervical cancer-associated transcriptome data and reporter biomolecules were identified at RNA (mRNA, miRNA), protein (receptor, transcription factor, etc.), and metabolite levels by the integration of gene expression profiles with genome-scale biomolecular networks. This approach revealed already-known biomarkers, tumor suppressors and oncogenes in cervical cancer as well as various receptors (e.g. ephrin receptors EPHA4, EPHA5, and EPHB2; endothelin receptors EDNRA and EDNRB; nuclear receptors NCOA3, NR2C1, and NR2C2), miRNAs (e.g., miR-192-5p, miR-193b-3p, and miR-215-5p), transcription factors (particularly E2F4, ETS1, and CUTL1), other proteins (e.g., KAT2B, PARP1, CDK1, GSK3B, WNK1, and CRYAB), and metabolites (particularly, arachidonic acids) as novel biomarker candidates and potential therapeutic targets. The differential expression profiles of all reporter biomolecules were cross-validated in independent RNA-Seq and miRNA-Seq datasets, and the prognostic power of several reporter biomolecules, including KAT2B, PCNA, CD86, miR-192-5p and miR-215-5p was also demonstrated. In this study, we reported valuable data for further experimental and clinical efforts, because the proposed biomolecules have significant potential as systems biomarkers for screening or therapeutic purposes in cervical carcinoma.

Sun CC, Zhou Q, Hu W, et al.
Transcriptional E2F1/2/5/8 as potential targets and transcriptional E2F3/6/7 as new biomarkers for the prognosis of human lung carcinoma.
Aging (Albany NY). 2018; 10(5):973-987 [PubMed] Free Access to Full Article Related Publications
E2F is a group of genes that encode a family of transcription factors (TFs) in higher eukaryotes and participate in cell cycle regulation and DNA synthesis in mammalian cells. Evidence from cell lines, mouse models, and human tissues indicates that TFs are implicated in lung cancer (LC) tumorigenesis. However, the diverse expression patterns and prognostic values of eight E2Fs have yet to be elucidated. In the current study, we examined the transcriptional and survival data of E2Fs in patients with LC from ONCOMINE, GEPIA, Kaplan-Meier Plotter, and cBioPortal databases. We found that the expression levels of E2F1/2/3/5/6/7/8 were higher in lung adenocarcinoma and squamous cell lung carcinoma tissues than in lung tissues, whereas the expression level of E2F4 was lower in the former than in the latter. The expression levels of E2F2/4/5/7/8 were correlated with advanced tumor stage. Survival analysis using the Kaplan-Meier Plotter database revealed that the high transcription levels of E2F1/2/4/5/7/8 were associated with low relapse-free survival (RFS) in all of the patients with LC. Conversely, high E2F3/6 levels predicted high RFS in these patients. This study implied that E2F3/6/7 are potential targets of precision therapy for patients with LC and that E2F1/2/4/5/8 are new biomarkers for the prognosis of LC.

Wang J, Tian Y, Chen H, et al.
Key signaling pathways, genes and transcription factors associated with hepatocellular carcinoma.
Mol Med Rep. 2018; 17(6):8153-8160 [PubMed] Free Access to Full Article Related Publications
The purpose of the present study was to investigate the underlying molecular mechanism of hepatocellular carcinoma (HCC) using bioinformatics approaches. The microarray dataset GSE64041 was downloaded from the Gene Expression Omnibus database, which included 60 tumor liver samples and 60 matched control samples. Differentially expressed genes (DEGs) between HCC and control groups were identified. Then functional enrichment analyses, protein‑protein interaction (PPI) network, sub‑network and integrated transcription factor (TF)‑microRNA (miRNA)‑target network analyses were performed for these DEGs. A total of 378 DEGs were obtained, including 101 upregulated and 277 downregulated DEGs. In addition, functional enrichment analysis for DEGs in the sub‑network revealed 'cell division' and 'cell cycle' as key Gene Ontology (GO) terms and pathways. Topoisomerase (DNA) IIα (TOP2A) and integrin subunit α2 (ITGA2) were hub nodes in the PPI network. TOP2A, cyclin dependent kinase 1 (CDK1) and polo like kinase 1 (PLK1) were revealed to be hub nodes in the sub‑network. Finally, 4 TFs including forkhead box M1 (FOXM1), E2F transcription factor 4 (E2F4), SIN3 transcription regulator family member A (SIN3A) and transcription factor 7 like 1 (TCF7L1) were obtained through integrated network analysis. TOP2A, ITGA2, PLK1 and CDK1 may be key genes involved in HCC development. 'Cell division' and 'cell cycle' were indicated to act as key GO terms and Kyoto Encyclopedia of Genes and Genomes pathways in HCC. In addition, FOXM1, TCF7L1, E2F4 and SIN3A were revealed to be key TFs associated with HCC.

Luna Coronell JA, Sergelen K, Hofer P, et al.
The Immunome of Colon Cancer: Functional In Silico Analysis of Antigenic Proteins Deduced from IgG Microarray Profiling.
Genomics Proteomics Bioinformatics. 2018; 16(1):73-84 [PubMed] Free Access to Full Article Related Publications
Characterization of the colon cancer immunome and its autoantibody signature from differentially-reactive antigens (DIRAGs) could provide insights into aberrant cellular mechanisms or enriched networks associated with diseases. The purpose of this study was to characterize the antibody profile of plasma samples from 32 colorectal cancer (CRC) patients and 32 controls using proteins isolated from 15,417 human cDNA expression clones on microarrays. 671 unique DIRAGs were identified and 632 were more highly reactive in CRC samples. Bioinformatics analyses reveal that compared to control samples, the immunoproteomic IgG profiling of CRC samples is mainly associated with cell death, survival, and proliferation pathways, especially proteins involved in EIF2 and mTOR signaling. Ribosomal proteins (e.g., RPL7, RPL22, and RPL27A) and CRC-related genes such as APC, AXIN1, E2F4, MSH2, PMS2, and TP53 were highly enriched. In addition, differential pathways were observed between the CRC and control samples. Furthermore, 103 DIRAGs were reported in the SEREX antigen database, demonstrating our ability to identify known and new reactive antigens. We also found an overlap of 7 antigens with 48 "CRC genes." These data indicate that immunomics profiling on protein microarrays is able to reveal the complexity of immune responses in cancerous diseases and faithfully reflects the underlying pathology.

Arbi M, Pefani DE, Taraviras S, Lygerou Z
Controlling centriole numbers: Geminin family members as master regulators of centriole amplification and multiciliogenesis.
Chromosoma. 2018; 127(2):151-174 [PubMed] Related Publications
To ensure that the genetic material is accurately passed down to daughter cells during mitosis, dividing cells must duplicate their chromosomes and centrosomes once and only once per cell cycle. The same key steps-licensing, duplication, and segregation-control both the chromosome and the centrosome cycle, which must occur in concert to safeguard genome integrity. Aberrations in genome content or centrosome numbers lead to genomic instability and are linked to tumorigenesis. Such aberrations, however, can also be part of the normal life cycle of specific cell types. Multiciliated cells best exemplify the deviation from a normal centrosome cycle. They are post-mitotic cells which massively amplify their centrioles, bypassing the rule for once-per-cell-cycle centriole duplication. Hundreds of centrioles dock to the apical cell surface and generate motile cilia, whose concerted movement ensures fluid flow across epithelia. The early steps that control the generation of multiciliated cells have lately started to be elucidated. Geminin and the vertebrate-specific GemC1 and McIdas are distantly related coiled-coil proteins, initially identified as cell cycle regulators associated with the chromosome cycle. Geminin is required to ensure once-per-cell-cycle genome replication, while McIdas and GemC1 bind to Geminin and are implicated in DNA replication control. Recent findings highlight Geminin family members as early regulators of multiciliogenesis. GemC1 and McIdas specify the multiciliate cell fate by forming complexes with the E2F4/5 transcription factors to switch on a gene expression program leading to centriole amplification and cilia formation. Positive and negative interactions among Geminin family members may link cell cycle control to centriole amplification and multiciliogenesis, acting close to the point of transition from proliferation to differentiation. We review key steps of centrosome duplication and amplification, present the role of Geminin family members in the centrosome and chromosome cycle, and discuss links with disease.

Jiao J, Niu W, Wang Y, et al.
Prevalence of Aflatoxin-Associated
Cancer Prev Res (Phila). 2018; 11(2):103-112 [PubMed] Free Access to Full Article Related Publications
We aimed to determine whether aflatoxin dietary exposure plays a role in the high incidence of hepatocellular carcinoma (HCC) observed among Hispanics in South Texas. We measured

Zhu Y, Gu J, Li Y, et al.
MiR-17-5p enhances pancreatic cancer proliferation by altering cell cycle profiles via disruption of RBL2/E2F4-repressing complexes.
Cancer Lett. 2018; 412:59-68 [PubMed] Related Publications
The members of the miR-17-92 cluster are upregulated in various cancers and function as a cluster of oncogenic miRNA. Our study characterized a new function of miR-17-5p, a member of the miR-17-92 cluster, in regulating cell proliferation in pancreatic cancer. Our results indicate that miR-17-5p was up-regulated in pancreatic adenocarcinoma and directly targeted the retinoblastoma-like protein 2 (RBL2), a tumor suppressor belonging to the Rb family. High levels of miR-17-5p and low levels of RBL2 were associated with poor prognosis. RBL2 interacted with the transcription factor E2F4 and bound to the promoter regions of the E2F target genes. Disruption of the RBL2/E2F4 complex by miR-17-5p overexpression shifted the activity of E2F from gene repressing to gene activating, which induced cell cycle entry and proliferation. These results suggest that miR-17-5p promoted proliferation in pancreatic ductal adenocarcinoma cells (PDAC), and altered cell cycle profiles in vivo and in vitro, by disrupting the RBL2/E2F4-associated gene repressing complexes via direct targeting of RBL2. The new regulatory network, involving miR-17-5p and RBL2, emerges as a new target of PDAC treatment.

Souza TM, van den Beucken T, Kleinjans JCS, Jennen DGJ
Inferring transcription factor activity from microarray data reveals novel targets for toxicological investigations.
Toxicology. 2017; 389:101-107 [PubMed] Related Publications
Transcription factors (TFs) are important modulators of the inducible portion of the transcriptome, and therefore relevant in the context of exposure to exogenous compounds. Current approaches to predict the activity of TFs in biological systems are usually restricted to a few entities at a time due to low-throughput techniques targeting a limited fraction of annotated human TFs. Therefore, high-throughput alternatives may help to identify new targets of mechanistic and predictive value in toxicological investigations. In this study, we inferred the activity multiple TFs using publicly available microarray data from primary human hepatocytes exposed to hundreds of chemicals and evaluated these molecular profiles using multiple correspondence analysis. Our results demonstrate that the lowest dose and latest exposure time (24h) in a subset of chemicals generates a signature indicative of carcinogenicity possibly due to DNA-damaging properties. Furthermore, profiles from the earliest exposure time (2h) and highest dose creates clusters of chemicals implicated in the development of diverse forms of drug-induced liver injury (DILI). Both approaches yielded a number of TFs with similar activity across groups of chemicals, including TFs known in toxicological responses such as AhR, NFE2L2 (Nrf2), NF-κB and PPARG. FOXM1, IRF1 and E2F4 were some of the TFs identified that may be relevant in genotoxic carcinogenesis. SMADs (SMAD1, SMAD2, SMAD5) and KLF5 were identified as some of potentially new TFs whose inferred activities were linked to acute and progressive outcomes in DILI. In conclusion this study offers a novel mechanistic approach targeting TF activity during chemical exposure.

Gao B, Yu T, Xue D, et al.
A multidimensional integration analysis reveals potential bridging targets in the process of colorectal cancer liver metastasis.
PLoS One. 2017; 12(6):e0178760 [PubMed] Free Access to Full Article Related Publications
Approximately 9% of cancer-related deaths are caused by colorectal cancer. Liver metastasis is a major factor for the high colorectal cancer mortality rate. However, the molecular mechanism underlying colorectal cancer liver metastasis remains unclear. Using a global and multidimensional integration approach, we studied sequencing data, protein-protein interactions, and regulation of transcription factor and non-coding RNAs in primary tumor samples and liver metastasis samples to unveil the potential bridging molecules and the regulators that functionally link different stages of colorectal cancer liver metastasis. Primary tumor samples and liver metastasis samples had modules with significant overlap and crosstalk from which we identified several bridging genes (e.g. KNG1 and COX5B), transcription factors (e.g. E2F4 and CDX2), microRNAs (e.g. miR-590-3p and miR-203) and lncRNAs (e.g. lincIRX5 and lincFOXF1) that may play an important role in the process of colorectal cancer liver metastasis. This study enhances our understanding of the genetic alterations and transcriptional regulation that drive the metastatic process, but also provides the methodology to guide the studies on other metastatic cancers.

Mark KMK, Varn FS, Ung MH, et al.
The E2F4 prognostic signature predicts pathological response to neoadjuvant chemotherapy in breast cancer patients.
BMC Cancer. 2017; 17(1):306 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Neoadjuvant chemotherapy is a key component of breast cancer treatment regimens and pathologic complete response to this therapy varies among patients. This is presumably due to differences in the molecular mechanisms that underlie each tumor's disease pathology. Developing genomic clinical assays that accurately categorize responders from non-responders can provide patients with the most effective therapy for their individual disease.
METHODS: We applied our previously developed E2F4 genomic signature to predict neoadjuvant chemotherapy response in breast cancer. E2F4 individual regulatory activity scores were calculated for 1129 patient samples across 5 independent breast cancer neoadjuvant chemotherapy datasets. Accuracy of the E2F4 signature in predicting neoadjuvant chemotherapy response was compared to that of the Oncotype DX and MammaPrint predictive signatures.
RESULTS: In all datasets, E2F4 activity level was an accurate predictor of neoadjuvant chemotherapy response, with high E2F4 scores predictive of achieving pathologic complete response and low scores predictive of residual disease. These results remained significant even after stratifying patients by estrogen receptor (ER) status, tumor stage, and breast cancer molecular subtypes. Compared to the Oncotype DX and MammaPrint signatures, our E2F4 signature achieved similar performance in predicting neoadjuvant chemotherapy response, though all signatures performed better in ER+ tumors compared to ER- ones. The accuracy of our signature was reproducible across datasets and was maintained when refined from a 199-gene signature down to a clinic-friendly 33-gene panel.
CONCLUSION: Overall, we show that our E2F4 signature is accurate in predicting patient response to neoadjuvant chemotherapy. As this signature is more refined and comparable in performance to other clinically available gene expression assays in the prediction of neoadjuvant chemotherapy response, it should be considered when evaluating potential treatment options.

Wang SA, Wang YC, Chuang YP, et al.
EGF-mediated inhibition of ubiquitin-specific peptidase 24 expression has a crucial role in tumorigenesis.
Oncogene. 2017; 36(21):2930-2945 [PubMed] Free Access to Full Article Related Publications
In this study, several cancer-related proteins (Bax, p300, E2F4 and securin) have been proven to be substrates of ubiquitin-specific peptidase 24 (USP24), and relevance has been shown between USP24 and its substrates in samples from clinical lung cancer patients. Silencing USP24 increases the cancer formation by inhibiting cellular apoptosis and increasing cellular proliferation. Epidermal growth factor (EGF) treatment, and the Kras

Donaires FS, Godoy PR, Leandro GS, et al.
E2F transcription factors associated with up-regulated genes in glioblastoma.
Cancer Biomark. 2017; 18(2):199-208 [PubMed] Related Publications
BACKGROUND: Glioblastoma is considered to the most common and malignant brain tumor in adults. Patients have a median survival of approximately one year from diagnosis due to poor response to therapy.
OBJECTIVE: We applied bioinformatics approaches to predict transcription factors (TF) that are deregulated in glioblastoma in an attempt to point out molecular targets for therapy.
METHODS: Up-regulated genes in glioblastoma selected from public microarray data were submitted to two TF association analyses. Thereafter, the expression levels of TF obtained in the overlap of analyses were assessed by RT-qPCR carried out in seven glioblastoma cell lines (T98, U251, U138, U87, U343, M059J, and M059K).
RESULTS: E2F1 and E2F4 were highlighted in both TF analyses. However, only E2F1 was confirmed as significantly up-regulated in all glioblastoma cell lines in vitro.
CONCLUSION: E2F1 is a potential common regulator of differentially expressed genes in glioblastoma, despite the genetic heterogeneity of tumor cells.

Lee J, Jung JH, Chae YS, et al.
Long Noncoding RNA snaR Regulates Proliferation, Migration and Invasion of Triple-negative Breast Cancer Cells.
Anticancer Res. 2016; 36(12):6289-6295 [PubMed] Related Publications
AIM: We evaluated the role of long noncoding ribonucleic acid (lncRNA) in breast cancer cell lines by quantitative reverse transcription-polymerase change reaction.
MATERIALS AND METHODS: The effects of small NF90-associated RNA (snaR) with RNA interference on proliferation, migration and invasion of MDA-MB-231 cells were observed by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide, wound healing and transwell assay.
RESULTS: Among 90 lncRNAs, E2F transcription factor 4, p107/p130-binding (E2F4) antisense, insulin-like growth factor 2 antisense (IGF2AS), snaR, and small nucleolar RNA host gene 5 (SNHG5) were up-regulated in MDA-MB-231 and 7SK, antisense noncoding RNA in the INK4 locus (ANRIL), IGF2AS, Nespas, p53 mRNA, and snaR were up-regulated in MCF-7 cells. Down-regulation of snaR inhibited the proliferation, migration, and invasion of MDA-MD-231 breast cancer cells.
CONCLUSION: LncRNA snaR was found to be up-regulated in breast cancer cells, and the cancer progression of MDA-MB-231 cells was significantly suppressed by down-regulation of snaR. Therefore, snaR knockdown has potential as a treatment modality for triple-negative breast cancer.

Conley A, Minciacchi VR, Lee DH, et al.
High-throughput sequencing of two populations of extracellular vesicles provides an mRNA signature that can be detected in the circulation of breast cancer patients.
RNA Biol. 2017; 14(3):305-316 [PubMed] Free Access to Full Article Related Publications
Extracellular vesicles (EVs) contain a wide range of RNA types with a reported prevalence of non-coding RNA. To date a comprehensive characterization of the protein coding transcripts in EVs is still lacking. We performed RNA-Sequencing (RNA-Seq) of 2 EV populations and identified a small fraction of transcripts that were expressed at significantly different levels in large oncosomes and exosomes, suggesting they may mediate specialized functions. However, these 2 EV populations exhibited a common mRNA signature that, in comparison to their donor cells, was significantly enriched in mRNAs encoding E2F transcriptional targets and histone proteins. These mRNAs are primarily expressed in the S-phase of the cell cycle, suggesting that they may be packaged into EVs during S-phase. In silico analysis using subcellular compartment transcriptome data from the ENCODE cell line compendium revealed that EV mRNAs originate from a cytoplasmic RNA pool. The EV signature was independently identified in plasma of patients with breast cancer by RNA-Seq. Furthermore, several transcripts differentially expressed in EVs from patients versus controls mirrored differential expression between normal and breast cancer tissues. Altogether, this largest high-throughput profiling of EV mRNA demonstrates that EVs carry tumor-specific alterations and can be interrogated as a source of cancer-derived cargo.

Nagasawa T, Sugai T, Shoji T, et al.
Molecular Analysis of Single Tumor Glands Using the Crypt Isolation Method in Endometrial Carcinomas.
Int J Gynecol Cancer. 2016; 26(9):1658-1666 [PubMed] Related Publications
OBJECTIVE: Endometrial adenocarcinomas are characterized by the presence of many single tumor glands in which multiple genetic changes have accumulated. To elucidate the differences in molecular abnormalities among single tumor glands, individual tumor glands were analyzed and microsatellite alterations (loss of heterozygosity (LOH) and microsatellite instability [MSI]) were examined using the crypt isolation method in glands from each tumor from patients with endometrial carcinoma.
METHODS: Twenty-five patients with endometrial adenocarcinoma who underwent surgery were included in this study. We obtained cancerous individual isolated tumor glands from each patient using the crypt isolation method. For LOH and MSI analyses, we used 15 microsatellite markers (3p, 5q, 10q, 13q, 17p, 18q, BAT25, and BAT26) and the promoter regions of 6 genes (transforming growth factor beta receptor II, BAX, insulin-like growth factor II receptor, E2F4, MutS homolog 3, and MSH6).
RESULTS: Loss of heterozygosity was detected in 8 (32%) of 25 patients, and MSI was detected in 9 (36%) of 25 patients. Some MSI-positive carcinomas had LOH in single tumor gland samples, and the coexistence of LOH and MSI was confirmed. In 16 (64%) of 25 cases, intratumoral genetic heterogeneity among single tumor gland samples was detected.
CONCLUSIONS: By analyzing multiple single tumor glands within the same tumor, we found that endometrial adenocarcinoma was composed of various tumor glands with different molecular abnormalities, even in a limited region within the same tumor.

Hansen SN, Ehlers NS, Zhu S, et al.
The stepwise evolution of the exome during acquisition of docetaxel resistance in breast cancer cells.
BMC Genomics. 2016; 17:442 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Resistance to taxane-based therapy in breast cancer patients is a major clinical problem that may be addressed through insight of the genomic alterations leading to taxane resistance in breast cancer cells. In the current study we used whole exome sequencing to discover somatic genomic alterations, evolving across evolutionary stages during the acquisition of docetaxel resistance in breast cancer cell lines.
RESULTS: Two human breast cancer in vitro models (MCF-7 and MDA-MB-231) of the step-wise acquisition of docetaxel resistance were developed by exposing cells to 18 gradually increasing concentrations of docetaxel. Whole exome sequencing performed at five successive stages during this process was used to identify single point mutational events, insertions/deletions and copy number alterations associated with the acquisition of docetaxel resistance. Acquired coding variation undergoing positive selection and harboring characteristics likely to be functional were further prioritized using network-based approaches. A number of genomic changes were found to be undergoing evolutionary selection, some of which were likely to be functional. Of the five stages of progression toward resistance, most resistance relevant genomic variation appeared to arise midway towards fully resistant cells corresponding to passage 31 (5 nM docetaxel) for MDA-MB-231 and passage 16 (1.2 nM docetaxel) for MCF-7, and where the cells also exhibited a period of reduced growth rate or arrest, respectively. MCF-7 cell acquired several copy number gains on chromosome 7, including ABC transporter genes, including ABCB1 and ABCB4, as well as DMTF1, CLDN12, CROT, and SRI. For MDA-MB-231 numerous copy number losses on chromosome X involving more than 30 genes was observed. Of these genes, CASK, POLA1, PRDX4, MED14 and PIGA were highly prioritized by the applied network-based gene ranking approach. At higher docetaxel concentration MCF-7 subclones exhibited a copy number loss in E2F4, and the gene encoding this important transcription factor was down-regulated in MCF-7 resistant cells.
CONCLUSIONS: Our study of the evolution of acquired docetaxel resistance identified several genomic changes that might explain development of docetaxel resistance. Interestingly, the most relevant resistance-associated changes appeared to originate midway through the evolution towards fully resistant cell lines. Our data suggest that no single genomic event sufficiently predicts resistance to docetaxel, but require genomic alterations affecting multiple pathways that in concert establish the final resistance stage.

Ye C, Tao R, Cao Q, et al.
Whole-genome DNA methylation and hydroxymethylation profiling for HBV-related hepatocellular carcinoma.
Int J Oncol. 2016; 49(2):589-602 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a common solid tumor worldwide with a poor prognosis. Accumulating evidence has implicated important regulatory roles of epigenetic modifications in the occurrence and progression of HCC. In the present study, we analyzed 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) levels in the tumor tissues and paired adjacent peritumor tissues (APTs) from four individual HCC patients using a (hydroxy)methylated DNA immunoprecipitation approach combined with deep sequencing [(h)MeDIP-Seq]. Bioinformatics analysis revealed that the 5-mC levels in the promoter regions of 2796 genes and the 5-hmC levels in 507 genes differed significantly between HCC tissues and APTs. These differential genes were grouped into various clusters and pathways and found to be particularly enriched in the 'metabolic pathways' that include 'Glycolysis/gluconeogenesis', 'Oxidative phosphorylation' and 'Citrate cycle (TCA cycle)', implicating a potential role of metabolic alterations in HCC. Furthermore, 144 genes had both 5-mC and 5-hmC changes in HCC patients, and 10 of them (PCNA, MDM2, STAG1, E2F4, FGF4, FGF19, RHOBTB2, UBE2QL1, DCN and HSP90AA1) were enriched and interconnected in five pathways including the 'Cell cycle', 'Pathway in cancer', 'Ubiquitin mediated proteolysis', 'Melanoma' and 'Prostate cancer' pathways. The genome-wide mapping of 5-mC and 5-hmC in HCC tissues and APTs indicated that both 5-mC and 5-hmC epigenetic modifications play important roles in the regulation of HCC, and there may be some interconnections between them. Taken together, in the present study we conducted the first genome-wide mapping of DNA methylation combined with hydroxymethylation in HBV-related HCC and provided a series of potential novel epigenetic biomarkers for HCC.

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] Free Access to Full Article 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.

Fischer M, Quaas M, Nickel A, Engeland K
Indirect p53-dependent transcriptional repression of Survivin, CDC25C, and PLK1 genes requires the cyclin-dependent kinase inhibitor p21/CDKN1A and CDE/CHR promoter sites binding the DREAM complex.
Oncotarget. 2015; 6(39):41402-17 [PubMed] Free Access to Full Article Related Publications
The transcription factor p53 is central to cell cycle control by downregulation of cell cycle-promoting genes upon cell stress such as DNA damage. Survivin (BIRC5), CDC25C, and PLK1 encode important cell cycle regulators that are repressed following p53 activation. Here, we provide evidence that p53-dependent repression of these genes requires activation of p21 (CDKN1A, WAF1, CIP1). Chromatin immunoprecipitation (ChIP) data indicate that promoter binding of B-MYB switches to binding of E2F4 and p130 resulting in a replacement of the MMB (Myb-MuvB) by the DREAM complex. We demonstrate that this replacement depends on p21. Furthermore, transcriptional repression by p53 requires intact DREAM binding sites in the target promoters. The CDE and CHR cell cycle promoter elements are the sites for DREAM binding. These elements as well as the p53 response of Survivin, CDC25C, and PLK1 are evolutionarily conserved. No binding of p53 to these genes is detected by ChIP and mutation of proposed p53 binding sites does not alter the p53 response. Thus, a mechanism for direct p53-dependent transcriptional repression is not supported by the data. In contrast, repression by DREAM is consistent with most previous findings and unifies models based on p21-, E2F4-, p130-, and CDE/CHR-dependent repression by p53. In conclusion, the presented data suggest that the p53-p21-DREAM-CDE/CHR pathway regulates p53-dependent repression of Survivin, CDC25C, and PLK1.

Dodurga Y, Seçme M, Eroğlu C, et al.
Investigation of the effects of a sulfite molecule on human neuroblastoma cells via a novel oncogene URG4/URGCP.
Life Sci. 2015; 143:27-34 [PubMed] Related Publications
AIM: The aim of this study is to determine the anticancer effect of sulfite on SH-SY5Y neuroblastoma cells in vitro conditions and elucidate underlying molecular mechanism of sulfite and explore its therapeutic activity.
MAIN METHODS: In this study, cytotoxic effects of sulfite in SH-SY5Y cels were detected over time in a dose dependent manner with the IC50 doses ranging from 0.5 to 10 mM. Genotoxic effect of sulfite was shown by comet assay. IC50 doses in the SH-SY5Y cells were detected as 5 mM. Expression profiles of the target genes related to apoptosis and cell cycle control were determined by quantitative RT-PCR. Protein changes were determined by western blot analysis.
KEY FINDINGS: URG4/URGCP, CCND1, CCND2, CDK4, CDK6, E2F4 and BCL-2 gene expression levels were significantly reduced and RB1, TP53, BAX, BID, CASP2, CASP3, CASP9 and DIABLO gene expressions were significantly increased in dose group cells. The mechanism of this result may be related to sulfite dependent inhibition of cell cycle at the G1 phase by down-regulating URG4/URGCP or CCND1, CDK4, CDK6 gene expression and stimulating apoptosis via the intrinsic pathway. Sulfite suppressed invasion and colony formation in SH-SY5Y cell line using matrigel invasion chamber and colony formation assay, respectively.
SIGNIFICANCE: It is thought that sulfite demonstrates anticarcinogenesis activity by affecting cell cycle arrest, apoptosis s, invasion, and colony formation on SH-SY5Y cells. Sulfite may be an effective agent for treatment of neuroblastoma as a single agent or in combination with other agents.

Lawrenson K, Iversen ES, Tyrer J, et al.
Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer.
Carcinogenesis. 2015; 36(11):1341-53 [PubMed] Free Access to Full Article Related Publications
Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.

Gupta ED, Pachauri M, Ghosh PC, Rajam MV
Targeting polyamine biosynthetic pathway through RNAi causes the abrogation of MCF 7 breast cancer cell line.
Tumour Biol. 2016; 37(1):1159-71 [PubMed] Related Publications
The diamine putrescine and polyamines, spermidine (triamine) and spermine (tetraamine) are small organic polycations that play an indispensable role in key cellular processes such as the regulation of growth, differentiation, and macromolecular functions. Elevated levels of polyamines (PAs) have been shown to be one of the major factors involved in carcinogenesis. In this study, specific silencing of the expression of three genes of PA biosynthesis pathway, ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase (SAMDC), and spermidine synthase (SPDSYN) was achieved using RNA interference in MCF 7 breast cancer cell line. For optimizing the effective small interfering nucleic acid (siNA), three variants of ODC siNA [siRNA, locked nucleic acid (LNA)-modified siRNA, and siHybrid (RNA and DNA hybrid)] were used and a dose- and time-dependent study was conducted. The PA biosynthetic genes were targeted individually and in combination. RNAi-mediated reduction in the expression of PA biosynthesis genes resulted in distorted cell morphology, reduced cancer cell viability, and migration characteristic. The most promising results were observed with the combined treatment of siSPDSYN and siODC with 83 % cell growth inhibition. On analyzing the messenger RNA (mRNA) expression profile of the cell cycle and apoptosis-related genes, it was observed that RNAi against PA biosynthetic genes downregulated the expression of CDK8, CCNE2, CCNH, CCNT1, CCNT2, CCNF, PCNA, CCND1, and CDK2, and upregulated the expression of E2F4, BAX, FAS, TP53, CDKN1A, BAK1, CDKN1B, ATM, GRANB, and ATR genes when compared with control-transfected cells. These results suggest that the targeting polyamine biosynthesis through RNAi approach could be a promising strategy for breast cancer therapy and might be extended for therapy of other cancers.

Altinoz MA, Tunalı NE
Trinucleotide repeat expansions in human breast cancer-susceptibility genes: relevant targets for aspirin chemoprevention?
Clin Transl Oncol. 2016; 18(1):9-17 [PubMed] Related Publications
PURPOSE: Defining novel molecular mechanisms pertinent to aspirin chemoprevention of breast cancer (BC) and to explain controversial epidemiological results in this regard.
METHODS: Literature search in relevant databases with the following key words; aspirin, nucleotide repeat expansions, breast cancer. Human genome contains nucleotide repeat expansions and exon-1 of the androgen receptor gene AR contains a CAG string with an average of 20 repeats. Longer AR CAG repeats associate with lower AR protein functioning leading relatively higher estrogen receptor signals and higher risk of hormone receptor-positive BC. Nucleotide repeat expansions also exist in E2F4 and POLG genes in BC. In cell culture models, aspirin reduces CAG.CTG expansions in kidney cells and restores myogenic differentiation in cells obtained from tissues with myotonic dystrophy, a disorder caused by large CTG expansions.
CONCLUSIONS: We hypothesize that aspirin reduction of trinucleotide repeat expansions in breast cancer-susceptibility genes may be one of the relevant mechanisms of its chemopreventive effects.

Diniz MG, Silva Jde F, de Souza FT, et al.
Association between cell cycle gene transcription and tumor size in oral squamous cell carcinoma.
Tumour Biol. 2015; 36(12):9717-22 [PubMed] Related Publications
Higher tumor size correlates with poor prognosis and is an independent predictive survival factor in oral squamous cell carcinoma (OSCC) patients. However, the molecular events underlining OSCC tumor evolution are poorly understood. We aimed to investigate if large OSCC tumors show different cell cycle gene transcriptional signature compared to small tumors. Seventeen fresh OSCC tumor samples with different tumor sizes (T) were included in the study. Tumors were from the tongue or from the floor of the mouth, and only three patients were nonsmokers. Samples were categorized according to clinical tumor size in tumors ≤2 cm (T1, n = 5) or tumors >2 cm (T2, n = 9; T3, n = 2; T4, n = 1). The group of tumors ≤2 cm was considered the reference group, while the larger tumors were considered the test group. We assessed the expression of 84 cell cycle genes by qRT-PCR array and normalized it to the expression of two housekeeping genes. Results were analyzed according to the formula 2(^-DeltaCt). A five-fold change cutoff was used, and p values <0.05 were considered statistically significant. Ki-67 immunohistochemistry was performed to estimate cell proliferation index. Twenty-nine genes were downregulated in the test group (larger tumors) compared to the reference group (smaller tumors). Among these genes, 13 reached statistical significance: ANAPC4, CUL1, SUMO1, KPNA2, MAD2L2, CCNG2, E2F4, NBN, CUL2, PCNA, TFDP1, KNTC1, and ATR. Ki-67 labeling index was similar in both tumor groups. Our findings suggest that the transcriptional activity of specific cell cycle genes varies according to the size of OSCC tumor, which probably reflects tumor molecular evolution and adaptation to the microenvironment.

Eroğlu C, Seçme M, Bağcı G, Dodurga Y
Assessment of the anticancer mechanism of ferulic acid via cell cycle and apoptotic pathways in human prostate cancer cell lines.
Tumour Biol. 2015; 36(12):9437-46 [PubMed] Related Publications
Studies on genetic changes underlying prostate cancer and the possible signaling pathways are getting increased day by day, and new treatment methods are being searched for. The aim of the present study is to investigate the effects of ferulic acid (FA), a phenolic compound, on cell cycle, apoptosis, invasion, and colony formation in the PC-3 and LNCaP prostate cancer cells. The effect of FA on cell viability was determined via a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) method. Total RNA was isolated with Tri Reagent. Expression of 84 genes for both cell cycle and apoptosis separately was evaluated by reverse transcriptase PCR (RT-PCR). Protein expressions were evaluated by Western blot analysis. Furthermore, apoptotic effects of FA were observed with terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) assay. Effects of FA on cell invasion and colony formation were determined using Matrigel chamber and colony assay, respectively. The half maximal inhibitory concentration (IC50) dose of FA was found to be 300 μM in PC-3 cells and 500 μM in LNCaP cells. According to RT-PCR results, it was observed that FA inhibited cell proliferation by increasing the gene expressions of ATR, ATM, CDKN1A, CDKN1B, E2F4, RB1, and TP53 and decreasing the gene expressions of CCND1, CCND2, CCND3, CDK2, CDK4, and CDK6 in PC-3 cells. On the other hand, it was seen that FA suppressed cell proliferation by increasing in the gene expressions of CASP1, CASP2, CASP8, CYCS, FAS, FASLG, and TRADD and decreasing in the gene expressions of BCL2 and XIAP in LNCaP cells. In this study, protein expression of CDK4 and BCL2 genes significantly decreased in these cells. It could induce apoptosis in PC-3 and LNCaP cells. Also, it was observed that FA suppressed the invasion in PC-3 and LNCaP cells. Moreover, it suppressed the colony formation. In conclusion, it has been observed that FA may lead to cell cycle arrest in PC-3 cells while it may cause apoptosis in LNCaP cells.

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