Gene Summary

Gene:EIF4E; eukaryotic translation initiation factor 4E
Aliases: CBP, EIF4F, AUTS19, EIF4E1, eIF-4E, EIF4EL1
Summary:The protein encoded by this gene is a component of the eukaryotic translation initiation factor 4F complex, which recognizes the 7-methylguanosine cap structure at the 5' end of messenger RNAs. The encoded protein aids in translation initiation by recruiting ribosomes to the 5'-cap structure. Association of this protein with the 4F complex is the rate-limiting step in translation initiation. This gene acts as a proto-oncogene, and its expression and activation is associated with transformation and tumorigenesis. Several pseudogenes of this gene are found on other chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:eukaryotic translation initiation factor 4E
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (25)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 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.

  • Drug Resistance
  • Lung Cancer
  • Skin Cancer
  • Neoplastic Cell Transformation
  • Antineoplastic Agents
  • Phosphorylation
  • Cell Movement
  • Neoplasm Invasiveness
  • Chromosome 4
  • Down-Regulation
  • Cell Proliferation
  • EIF4E
  • Biomarkers, Tumor
  • TOR Serine-Threonine Kinases
  • Signal Transducing Adaptor Proteins
  • Multiprotein Complexes
  • Squamous Cell Carcinoma
  • RNA Interference
  • AKT1
  • Survival Rate
  • ras Proteins
  • p300-CBP Transcription Factors
  • Sirolimus
  • Phosphatidylinositol 3-Kinases
  • Apoptosis
  • Peptide Initiation Factors
  • Protein-Serine-Threonine Kinases
  • Cell Survival
  • siRNA
  • Neoplasm Proteins
  • RNA Caps
  • mechanistic target of rapamycin complex 1
  • Western Blotting
  • Virus Replication
  • Breast Cancer
  • Polymerase Chain Reaction
  • Phosphoproteins
  • Protein Biosynthesis
  • Immunohistochemistry
  • Cancer Gene Expression Regulation
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: EIF4E (cancer-related)

Liu M, Gong C, Xu R, et al.
MicroRNA-5195-3p enhances the chemosensitivity of triple-negative breast cancer to paclitaxel by downregulating EIF4A2.
Cell Mol Biol Lett. 2019; 24:47 [PubMed] Free Access to Full Article Related Publications
Background: Chemotherapy based on paclitaxel (PTX) is the standard treatment for a range of cancers, including triple-negative breast cancer (TNBC), but the increasing development of resistance has reduced/has negatively impacted its clinical utility. A previous study demonstrated that miR-5195-3p could suppress lung cancer cell growth. This study was designed to investigate whether miR-5195-3p attenuates chemoresistance to PTX by regulating target genes in TNBC cells.
Methods: The study used both PTX-resistant tumor tissues and PTX-resistant TNBC cell lines. The expression of miR-5195-3p was determined using quantitative real-time PCR. Cell viability, cell cycle distribution and apoptosis were analyzed using CCK-8 and flow cytometry assays. The target genes of miR-5195-3p were predicted with bioinformatics analysis and confirmed using the luciferase reporter assay.
Results: MiR-5195-3p expression was lower in PTX-resistant tumor tissues and PTX-resistant TNBC cell lines. Upregulation of miR-5195-3p enhanced the sensitivity of PTX-resistant TNBC cells to PTX treatment. EIF4A2 was confirmed as a potential target of miR-5195-3p. EIF4A2 knockdown imitated the effects of miR-5195-3p on chemosensitivity, while restoration of EIF4A2 rescued them.
Conclusion: These data demonstrate that miR-5195-3p might be a potential therapeutic target to reverse chemoresistance in TNBC through its targeting of EIF4A2.

Qi NN, Tian S, Li X, et al.
Up-regulation of microRNA-496 suppresses proliferation, invasion, migration and in vivo tumorigenicity of human osteosarcoma cells by targeting eIF4E.
Biochimie. 2019; 163:1-11 [PubMed] Related Publications
Osteosarcoma is an aggressive bone tumor characterized by a high level of genetic instability and recurring DNA deletions and amplifications. This study aims to investigate how microRNA-496 (miR-496) affects proliferation, invasion, and migration of human osteosarcoma (OS) cells and in vivo tumorigenicity by targeting eukaryotic translation initiation factor 4E (eIF4E). Microarray-based gene expression profiling involving OS was used in order to identify differentially expressed genes. After that, the interaction between miR-496 expression and OS patients' survival rate was determined. The expression pattern of miR-496 and eIF4E was determined in OS tissues and cells, and their potential relationship was further analyzed by using the dual luciferase reporter gene assay. With the purpose of identifying the functional role miR-496 in OS, cell proliferation, migration, and invasion were measured in cells treated with miR-496 mimic or inhibitor. A nude mouse model was constructed in order to investigate the regulatory effects of miR-496 on tumor growth in vivo by regulating eIF4E. OS cells exhibited a down-regulated expression of miR-496 and an up-regulated expression of eIF4E. miR-496 expression was positively correlated to OS patients' survival rate. Bioinformatics analysis suggested eIF4E would be a direct target of miR-496, and the expression of eIF4E was inhibited by overexpression of miR-496. miR-496 elevation was found to exert suppressive effects on OS cell proliferation, migration and invasion in vitro and tumor growth in vivo, with the effects being reversed using miR-496 depletion. Altogether, the above findings support a conclusion that miR-496 could work as a tumor suppressor in OS through down-regulation of eIF4E. This study may provide a novel target for treatment of OS.

Mao Y, Zhang L, Li Y
circEIF4G2 modulates the malignant features of cervical cancer via the miR‑218/HOXA1 pathway.
Mol Med Rep. 2019; 19(5):3714-3722 [PubMed] Free Access to Full Article Related Publications
Circular RNAs (circRNAs) serve important roles in tumorigenesis and may be used as novel molecular biomarkers for clinical diagnosis. However, the role and molecular mechanisms of circRNAs in cervical cancer (CC) remain unknown. In the present study, circRNA isoform of eukaryotic translation initiation factor 4γ2 (circEIF4G2) was revealed to be significantly upregulated in CC tissues and cell lines. Furthermore, increased expression of circEIF4G2 was associated with poor prognosis in patients with CC. circEIF4G2 knockdown suppressed the malignant features of CC cells, including cell proliferation, colony formation, migration and invasion. Additionally, circEIF4G2 was identified to serve as a sponge for microRNA‑218 (miR‑218), which targeted homeobox A1 (HOXA1). Furthermore, circEIF4G2 may increase the expression levels of HOXA1 by sponging miR‑218. Rescue experiments suggested that transfection with a miR‑218 inhibitor attenuated the inhibitory effects of circEIF4G2 knockdown on cell proliferation, migration and invasion. Furthermore, silencing HOXA1 reversed the effects of the miR‑218 inhibitor on CC cells. Collectively, the present findings suggested that circEIF4G2 promoted cell proliferation and migration via the miR‑218/HOXA1 pathway.

Ma X, Li B, Liu J, et al.
Phosphoglycerate dehydrogenase promotes pancreatic cancer development by interacting with eIF4A1 and eIF4E.
J Exp Clin Cancer Res. 2019; 38(1):66 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Pancreatic cancer is one of the most malignant cancers. The overall 5-year survival rate of its patients is 8%, the lowest among major cancer types. It is very urgent to study the development mechanisms of this cancer and provide potential targets for therapeutics design. Glucose, one of the most essential nutrients, is highly exploited for aerobic glycolysis in tumor cells to provide building blocks. However, the glucose consumption manner in pancreatic cancer cells is unclear. And the mechanism of the substantial metabolic pathway promoting pancreatic cancer development is also unrevealed.

Chen F, Qi S, Zhang X, et al.
lncRNA PLAC2 activated by H3K27 acetylation promotes cell proliferation and invasion via the activation of Wnt/β‑catenin pathway in oral squamous cell carcinoma.
Int J Oncol. 2019; 54(4):1183-1194 [PubMed] Free Access to Full Article Related Publications
As a new group of important effector molecules involved in multiple cancer types, including breast cancer, lung cancer and oral squamous cell carcinoma, long noncoding RNAs (lncRNAs) have attracted considerable attention recently. However, the underlying cause that induces the dysregulated lncRNAs in cancer remains poorly understood. In the present study, the regulatory model of the lncRNA placenta‑specific protein 2 (PLAC2) upregulation in oral squamous cell carcinoma (OSCC) was investigated and its biological functions in OSCC malignant progression was identified. A reverse transcription‑quantitative polymerase chain reaction assay identified that PLAC2 is upregulated in OSCC cell lines and primary tissue samples. Furthermore, bioinformatic analysis followed by chromatin immunoprecipitation verified an enriched histone H3 on lysine 27 (H3K27) acetylation (H3K27ac) at the promoter region of the PLAC2 gene. Knockdown of cAMP‑response element binding protein‑binding protein (CBP) significantly reduced the enrichment level of H3K27ac, and thereby induced a decreased expression of PLAC2. Functionally, overexpression of PLAC2 promotes OSCC cell proliferation, migration and invasion, whereas knockdown of PLAC2 exerted an opposite effect. Furthermore, the Wnt/β‑catenin signaling pathway was activated by PLAC2 and mediated the PLAC2‑induced malignant progress of OSCC. In conclusion, the present results indicated that lncRNA PLAC2 is transcriptionally activated by H3K27ac modification at the promoter region in OSCC, and promotes cell growth and metastasis via activating Wnt/β‑catenin signaling pathway. Therefore, PLAC2 may serve as a promising biomarker for OSCC prognosis and therapy.

Dong H, Hu J, Zou K, et al.
Activation of LncRNA TINCR by H3K27 acetylation promotes Trastuzumab resistance and epithelial-mesenchymal transition by targeting MicroRNA-125b in breast Cancer.
Mol Cancer. 2019; 18(1):3 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Trastuzumab resistance followed by metastasis is a major obstacle for improving the clinical outcome of patients with advanced human epidermal growth factor receptor 2-positive (HER-2+) breast cancer. While long non-coding RNAs (lncRNAs) can modulate cell behavior, the contribution of these RNAs in trastuzumab resistance and metastasis of HER-2+ breast cancer is not well known. In this study, we sought to identify the regulatory role of lncRNA in trastuzumab resistance and accompanied Epithelial-mesenchymal Transition (EMT) process in advanced HER-2+ breast cancer.
METHODS: Trastuzumab-resistant SKBR-3-TR and BT474-TR cell lines were established by grafting SKBR-3 and BT474 cells into mouse models and subjected to trastuzumab treatment. LncRNA microarray followed by quantitative reverse transcription PCR (qRT-PCR) was carried out to verify the differentially expressed lncRNAs. Western blotting, bioinformatics analysis, immunofluorescence assay and immunoprecipitation assays (ChIP and RIP) were performed to identify the involvement and functional interactions between H3K27 acetylation and terminal differentiation-induced non-coding RNA (TINCR) or between TINCR and its downstream genes including miR-125b, HER-2 and Snail-1. In addition, a series of in vitro and in vivo assays were performed to assess the functions of TINCR.
RESULTS: An increase in both, IC
CONCLUSION: TINCR could promote trastuzumab resistance and the accompanied EMT process in breast cancer. Therefore, TINCR might be a potential indicator for prognosis and a therapeutic target to enhance the clinical efficacy of trastuzumab treatment.

Cuesta R, Berman AY, Alayev A, Holz MK
Estrogen receptor α promotes protein synthesis by fine-tuning the expression of the eukaryotic translation initiation factor 3 subunit f (eIF3f).
J Biol Chem. 2019; 294(7):2267-2278 [PubMed] Article available free on PMC after 15/02/2020 Related Publications
Approximately two thirds of all breast cancer cases are estrogen receptor (ER)-positive. The treatment of this breast cancer subtype with endocrine therapies is effective in the adjuvant and recurrent settings. However, their effectiveness is compromised by the emergence of intrinsic or acquired resistance. Thus, identification of new molecular targets can significantly contribute to the development of novel therapeutic strategies. In recent years, many studies have implicated aberrant levels of translation initiation factors in cancer etiology and provided evidence that identifies these factors as promising therapeutic targets. Accordingly, we observed reduced levels of the eIF3 subunit eIF3f in ER-positive breast cancer cells compared with ER-negative cells, and determined that low eIF3f levels are required for proper proliferation and survival of ER-positive MCF7 cells. The expression of eIF3f is tightly controlled by ERα at the transcriptional (genomic pathway) and translational (nongenomic pathway) level. Specifically, estrogen-bound ERα represses transcription of the

MacFawn I, Wilson H, Selth LA, et al.
Grainyhead-like-2 confers NK-sensitivity through interactions with epigenetic modifiers.
Mol Immunol. 2019; 105:137-149 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Natural Killer (NK) cells suppress tumor initiation and metastasis. Most carcinomas are heterogeneous mixtures of epithelial, mesenchymal and hybrid tumor cells, but the relationships of these phenotypes to NK susceptibility are understood incompletely. Grainyhead-like-2 (GRHL2) is a master programmer of the epithelial phenotype, that is obligatorily down-regulated during experimentally induced Epithelial-Mesenchymal Transition (EMT). Here, we utilize GRHL2 re-expression to discover unifying molecular mechanisms that link the epithelial phenotype with NK-sensitivity. GRHL2 enhanced the expression of ICAM-1, augmenting NK-target cell synaptogenesis and NK killing of target cells. The expression of multiple interferon response genes, including ICAM1, anti-correlated with EMT. We identified two novel GRHL2-interacting proteins, the histone methyltransferases KMT2C and KMT2D. Mesenchymal-epithelial transition, NK-sensitization and ICAM-1 expression were promoted by GRHL2-KMT2C/D interactions and by GRHL2 inhibition of p300, revealing novel and potentially targetable epigenetic mechanisms connecting the epithelial phenotype with target cell susceptibility to NK killing.

Urtishak KA, Wang LS, Culjkovic-Kraljacic B, et al.
Targeting EIF4E signaling with ribavirin in infant acute lymphoblastic leukemia.
Oncogene. 2019; 38(13):2241-2262 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
The poor outcomes in infant acute lymphoblastic leukemia (ALL) necessitate new treatments. Here we discover that EIF4E protein is elevated in most cases of infant ALL and test EIF4E targeting by the repurposed antiviral agent ribavirin, which has anticancer properties through EIF4E inhibition, as a potential treatment. We find that ribavirin treatment of actively dividing infant ALL cells on bone marrow stromal cells (BMSCs) at clinically achievable concentrations causes robust proliferation inhibition in proportion with EIF4E expression. Further, we find that ribavirin treatment of KMT2A-rearranged (KMT2A-R) infant ALL cells and the KMT2A-AFF1 cell line RS4:11 inhibits EIF4E, leading to decreases in oncogenic EIF4E-regulated cell growth and survival proteins. In ribavirin-sensitive KMT2A-R infant ALL cells and RS4:11 cells, EIF4E-regulated proteins with reduced levels of expression following ribavirin treatment include MYC, MCL1, NBN, BCL2 and BIRC5. Ribavirin-treated RS4:11 cells exhibit impaired EIF4E-dependent nuclear to cytoplasmic export and/or translation of the corresponding mRNAs, as well as reduced phosphorylation of the p-AKT1, p-EIF4EBP1, p-RPS6 and p-EIF4E signaling proteins. This leads to an S-phase cell cycle arrest in RS4:11 cells corresponding to the decreased proliferation. Ribavirin causes nuclear EIF4E to re-localize to the cytoplasm in KMT2A-AFF1 infant ALL and RS4:11 cells, providing further evidence for EIF4E inhibition. Ribavirin slows increases in peripheral blasts in KMT2A-R infant ALL xenograft-bearing mice. Ribavirin cooperates with chemotherapy, particularly L-asparaginase, in reducing live KMT2A-AFF1 infant ALL cells in BMSC co-cultures. This work establishes that EIF4E is broadly elevated across infant ALL and that clinically relevant ribavirin exposures have preclinical activity and effectively inhibit EIF4E in KMT2A-R cases, suggesting promise in EIF4E targeting using ribavirin as a means of treatment.

Rivera-Calderón LG, Fonseca-Alves CE, Kobayashi PE, et al.
p-mTOR, p-4EBP-1 and eIF4E expression in canine prostatic carcinoma.
Res Vet Sci. 2019; 122:86-92 [PubMed] Related Publications
The mTOR/4E-BP1/eIF4E pathway plays important roles in the neoplastic transformation process and in tumour growth. In men, the mTOR/4E-BP1/eIF4E pathway was described as altered in different tumours, including prostate cancer (PC). Apart from humans, the dog is the only species that develops PC with high frequency and is considered a good model for comparative oncology initiatives. Due to limited information on this pathway in canine tumours, this study aimed to investigate mTOR, 4E-BP1 and eIF4E gene and protein expression in canine PC, as well as in metastatic and normal prostatic tissues, and to evaluate the correlations between gene/protein expression and Gleason score (GS) in PC. A total of 35 formalin-fixed paraffin-embedded (FFPE) samples, including 13 of normal prostatic tissue, 17 PC samples and 5 metastasis samples, were evaluated by immunohistochemistry and qPCR. mTOR gene mutation in the kinase domain was also investigated. We identified higher p-mTOR and eIF4E protein levels in canine PC with higher GS values (≥ 8) and a significant positive correlation in expression between these proteins. eIF4E overexpression was observed in metastasis relative to expression in normal samples. Our data suggest that p-mTOR and eIF4E expression is positively correlated with GS in canine PC, similar to the pattern in humans. More studies of the mTOR/4EBP1/eIF4E pathway should be performed to identify possible correlations of the proteins involved with clinical and pathologic findings in canine PC and the roles of these proteins as therapeutic targets for the treatment of canine PC.

Chen J, Xu X, Chen J
Clinically relevant concentration of anti-viral drug ribavirin selectively targets pediatric osteosarcoma and increases chemosensitivity.
Biochem Biophys Res Commun. 2018; 506(3):604-610 [PubMed] Related Publications
Ribavirin is an anti-viral drug but has recently gained attention as a potential candidate for cancer treatment. In line with these efforts, our work is the first to demonstrate that ribavirin, at clinically relevant concentration, selectively targets pediatric osteosarcoma and increases chemosensitivity. Using preclinical osteosarcoma cell and xenograft models, we found that ribavirin is active against osteosarcoma bulk and subpopulations with highly proliferative and invasive properties via inhibiting growth, inducing apoptosis and suppressing colony formation. At the same concentrations, ribavirin either did not or affected human normal osteoblastic cell and fibroblast cells in a less extent than osteosarcoma cells. Notably, the combination of ribavirin with doxorubicin resulted in greater efficacy than single drug alone. The combination completely arrested the osteosarcoma growth in vivo throughout the whole duration of drug treatment. We further showed that ribavirin acted on osteosarcoma largely via targeting eIF4E. In addition to eIF4E, ribavirin also modulated phosphorylation of Erk and expression of EZH2 and Snail without affecting Akt and mTOR. Lastly, we found that eIF4E expression and phosphorylation were elevated in osteosarcoma compared to normal cells, which might explain the selective anti-osteosarcoma activity of ribavirin. eIF4E depletion mimics the inhibitory effects of ribavirin, further confirm that eIF4E is the essential target of ribavirin in osteosarcoma. Our work provides fundamental evidence of repurposing ribavirin for the treatment of osteosarcoma. Our findings also highlight the therapeutic value of inhibiting eIF4E in osteosarcoma.

Song Y, Wang R, Li LW, et al.
Long non-coding RNA HOTAIR mediates the switching of histone H3 lysine 27 acetylation to methylation to promote epithelial-to-mesenchymal transition in gastric cancer.
Int J Oncol. 2019; 54(1):77-86 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
HOX transcript antisense intergenic RNA (HOTAIR), a well‑known long non‑coding RNA, plays an important role in the regulation of epithelial‑to‑mesenchymal transition (EMT). In this study, we propose a novel mechanism through which HOTAIR promotes EMT by switching histone H3 lysine 27 acetylation to methylation at the E‑cadherin promoter, which induces the transcriptional inhibition of E‑cadherin. HOTAIR recruits polycomb repressive complex 2 (PRC2) to catalyze H3K27me3; however, whether HOTAIR is associated with the acetylation of histone H3 lysine 27, a marker of transcriptional activation, and the mechanisms through which HOTAIR triggers the metastasis of gastric cancer (GC) by epigenetic regulation remain largely unknown. In this study, HOTAIR knockdown significantly reversed EMT by increasing the expression of E‑cadherin in GC cells. Additionally, the loss of PRC2 activity induced by HOTAIR knockdown resulted in a global decrease in H3K27 methylation and an increase in H3K27 acetylation. Furthermore, HOTAIR recruits PRC2 (which consists of H3K27 methyltransferase EZH2, SUZ12 and EED), which may inhibit the reaction between the acetyltransferase CBP and H3K27 acetylation. On the whole, the findings of this study suggested that the HOTAIR‑mediated acetylation to methylation switch was associated with the transcriptional inhibition of E‑cadherin. HOTAIR can promote the development of GC through the epigenetic regulation of E‑cadherin, switching the state of the E‑cadherin promoter from the transcriptionally active to the transcriptionally repressive state.

Subbaramaiah K, Iyengar NM, Morrow M, et al.
Prostaglandin E
J Biol Chem. 2019; 294(1):361-371 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Obesity increases the risk of hormone receptor-positive breast cancer in postmenopausal women. Levels of aromatase, the rate-limiting enzyme in estrogen biosynthesis, are increased in the breast tissue of obese women. Both prostaglandin E

Song J, Yuan C, Yang J, et al.
Novel flavagline-like compounds with potent Fli-1 inhibitory activity suppress diverse types of leukemia.
FEBS J. 2018; 285(24):4631-4645 [PubMed] Related Publications
E26 transformation-specific (ETS) gene family contains a common DNA-binding domain, the ETS domain, responsible for sequence-specific DNA recognition on target promoters. The Fli-1 oncogene, a member of ETS gene family, plays a critical role in hematopoiesis and is overexpressed in diverse hematological malignancies. This ETS transcription factor regulates genes controlling several hallmarks of cancer and thus represents an excellent target for cancer therapy. By screening compounds isolated from the medicinal plant Dysoxylum binectariferum in China, we identified two chemically related flavagline-like compounds including 4'-demethoxy-3',4'-methylenedioxyrocaglaol and rocaglaol that strongly inhibited Fli-1 transactivation ability. These compounds altered expression of Fli-1 target genes including GATA1, EKLF, SHIP1, and BCL2. Consequently, the flavagline-like compounds suppressed proliferation, induced apoptosis, and promoted erythroid differentiation of leukemic cells in culture. These compounds also suppressed erythroleukemogenesis in vivo in a Fli-1-driven mouse model. Mechanistically, the compounds blocked c-Raf-MEK-MAPK/ERK signaling, reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), and inhibited Fli-1 protein synthesis. Consistent with its high expression in myelomas, B-cell lymphoma, and B chronic lymphocytic leukemia (B-CLL), pharmacological inhibition of Fli-1 by the flavagline-like compounds or genetic knock-down via shRNA significantly hindered proliferation of corresponding cell lines and patients' samples. These results uncover a critical role of Fli-1 in growth and survival of various hematological malignancies and point to flavagline-like agents as lead compounds for the development of anti-Fli-1 drugs to treat leukemias/lymphomas overexpressing Fli-1.

Cerezo M, Guemiri R, Druillennec S, et al.
Translational control of tumor immune escape via the eIF4F-STAT1-PD-L1 axis in melanoma.
Nat Med. 2018; 24(12):1877-1886 [PubMed] Related Publications
Preventing the immune escape of tumor cells by blocking inhibitory checkpoints, such as the interaction between programmed death ligand-1 (PD-L1) and programmed death-1 (PD-1) receptor, is a powerful anticancer approach. However, many patients do not respond to checkpoint blockade. Tumor PD-L1 expression is a potential efficacy biomarker, but the complex mechanisms underlying its regulation are not completely understood. Here, we show that the eukaryotic translation initiation complex, eIF4F, which binds the 5' cap of mRNAs, regulates the surface expression of interferon-γ-induced PD-L1 on cancer cells by regulating translation of the mRNA encoding the signal transducer and activator of transcription 1 (STAT1) transcription factor. eIF4F complex formation correlates with response to immunotherapy in human melanoma. Pharmacological inhibition of eIF4A, the RNA helicase component of eIF4F, elicits powerful antitumor immune-mediated effects via PD-L1 downregulation. Thus, eIF4A inhibitors, in development as anticancer drugs, may also act as cancer immunotherapies.

Devan J, Janikova A, Mraz M
New concepts in follicular lymphoma biology: From BCL2 to epigenetic regulators and non-coding RNAs.
Semin Oncol. 2018; 45(5-6):291-302 [PubMed] Related Publications
The molecular pathogenesis of follicular lymphoma (FL) was partially revealed 3 decades ago, with the discovery of the translocation that brings BCL2 under the influence of immunoglobulin heavy chain enhancers in a vast majority of cases. Despite the importance of this seminal observation, it has become increasingly clear that additional genetic alterations need to occur to trigger neoplastic transformation and disease progression. The evolution of FL involves developmental arrest and disruption of the normal function of one or more of epigenetic regulators including KMT2D/MLL2, EZH2, CBP/CREBBP, p300/EP300, and HIST1H1 in >95% of cases. B-cells "arrested" in germinal centers acquire dozens of additional genetic aberrations that influence key pathways controlling their physiological development including B Cell Receptor (BCR) signaling, PI3K/AKT, TLR, mTOR, NF-κB, JAK/STAT, MAPK, CD40/CD40L, chemokine, and interleukin signaling. Additionally, most cases of FL do not result from linear accumulation of genomic aberrations, but rather evolve from a common progenitor cell population by diverse evolution, creating multiple FL subclones in one patient. Moreover, one of the subclones might acquire a combination of aberrations involving genes controlling cell survival and proliferation including MDM2, CDKN2A/B, BCL6, MYC, TP53, β2M, FOXO1, MYD88, STAT3, or miR-17-92, and this can lead to the transformation of an initially indolent FL to an aggressive lymphoma (2%-3% risk per year). The complexity of the disease is also underscored by the importance of its interactions with the microenvironment that can substantially influence disease development and prognosis. Interpreting individual aberrations in relation to their impact on normal processes, their frequency, position in the disease evolution, and the consequences of their (co)occurrence, are the basis for understanding FL pathogenesis. This is necessary for the identification of patients with risk of early progression or transformation, for the development of novel targeted therapies, and for personalized treatment approaches. In this review, we summarize recent knowledge of molecular pathways and microenvironmental components involved in FL biology, and discuss them in the context of physiological B-cell development, FL evolution, and targeted therapies.

Shao G, Liu Y, Ma T, et al.
GCN5 inhibition prevents IL-6-induced prostate cancer metastases through PI3K/PTEN/Akt signaling by inactivating Egr-1.
Biosci Rep. 2018; 38(6) [PubMed] Article available free on PMC after 04/01/2020 Related Publications
General control non-derepressible 5 (GCN5) is ectopically expressed in different types of human cancer and association with the carcinogenesis, development, and poor prognosis of cancers. The present study was aimed to investigate the potential role and related mechanisms of GCN5 in IL-6-treated prostate cancer (PCa) cell. The results showed that an elevated GCN5 expression was stimulated by IL-6. Knockdown of GCN5 significantly inhibited IL-6-driven proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). Moreover, early growth response-1 (Egr-1) expression was elevated by IL-6 treatment and GCN5 siRNA down-regulated the expression of Egr-1. Furthermore, overexpression of Egr-1 attenuated the effects of GCN5 silence on cell proliferation, migration, invasion, and EMT in PCa. Besides, knockdown of GCN5 resulted in the down-regulation of p-Akt and up-regulation of PTEN, which was partly impeded by Egr-1 overexpression. The effects of GCN5 overexpression on cell proliferation and invasion were suppressed by LY294002, In conclusion, these data demonstrated the negative effect of up-regulated GCN5 in IL-6-induced metastasis and EMT in PCa cells through PI3K/PTEN/Akt signaling pathway down-regulating Egr-1 expression.

Zhang H, Wang Y, Dou J, et al.
Acetylation of AGO2 promotes cancer progression by increasing oncogenic miR-19b biogenesis.
Oncogene. 2019; 38(9):1410-1431 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Argonaute2 (AGO2) is an effector of small RNA mediated gene silencing. Increasing evidence show that post-translational modifications of AGO2 can change miRNA activity at specific or global levels. Among the six mature miRNAs that are encoded by miR-17-92, miR-19b1 is the most powerful to exert the oncogenic properties of the entire cluster. Here we identify that AGO2 can be acetylated by P300/CBP and deacetylated by HDAC7, and that acetylation occurs at three sites K720, K493, and K355. Mutation of K493R/K720R, but not K355R at AGO2, inhibits miR-19b biogenesis. We demonstrate that acetylation of AGO2 specifically increases its recruiting pre-miR-19b1 to form the miPDC (miRNA precursor deposit complex), thereby to enhance miR-19b maturation. The motif UGUGUG in the terminal-loop of pre-miR-19b1, as a specific processing feature that is recognized and bound by acetylated AGO2, is essential for the assembly of miRISC (miRNA-induced silencing complex) loading complex. Analyses on public clinical data, xenograft mouse models, and IHC and ISH staining of lung cancer tissues, further confirm that the high levels of both AGO2 acetylation and miR-19b correlate with poor prognosis in lung cancer patients. Our finding reveals a novel function of AGO2 acetylation in increasing oncogenic miR-19b biogenesis and suggests that modulation of AGO2 acetylation has potential clinical implications.

Ichiyanagi O, Naito S, Ito H, et al.
Levels of 4EBP1/eIF4E Activation in Renal Cell Carcinoma Could Differentially Predict Its Early and Late Recurrence.
Clin Genitourin Cancer. 2018; 16(5):e1029-e1058 [PubMed] Related Publications
BACKGROUND: The objective was to explore the predictive markers of late recurrence (LR) > 5 years after curative nephrectomy for renal cell carcinoma (RCC).
PATIENTS AND METHODS: We retrospectively examined the data from 303 patients with localized clear cell RCC treated surgically at our institution from 1993 to 2011. Activation of the eukaryotic initiation factor (eIF)4E-binding protein 1 (4EBP1)/eIF4E axis at the mammalian target of rapamycin complex 1 (mTORC1) was evaluated in the tumor specimens. Weak, intermediate, and strong immunohistochemistry staining grades were defined for 4EBP1, phosphorylated 4EBP1, and eIF4E. The effects of clinicopathologic factors and activation level grades on tumor recurrence were analyzed using multivariate Cox regression models. To validate the present findings, we investigated clinical data from The Cancer Genome Atlas and protein/phosphoprotein data from corresponding patients from The Cancer Proteome Atlas.
RESULTS: Of the 303 patients, 31 and 16 patients developed early recurrence (ER, ≤ 5 years) and LR, respectively. The activation levels were comparable among the subcategories of pathologic TN stage, Fuhrman grade, and microvascular and capsular invasion. Pathologic stage ≥ T1b, Fuhrman grade 3/4, and an intermediate or strong activation level correlated significantly with overall recurrence and ER. Strong activation of the axis and pathologic stage ≥ T1b were identified as independent predictors of LR. Only 2 patients with weak activation experienced recurrence (1 each with ER and LR). Similar results were confirmed by the analyses of The Cancer Genome Atlas and The Cancer Proteome Atlas data.
CONCLUSION: The activation level of the axis in RCC tissues could independently predict for recurrence and differentially affect the timing of recurrence.

Lu W, Xiong H, Chen Y, et al.
Discovery and biological evaluation of thiobarbituric derivatives as potent p300/CBP inhibitors.
Bioorg Med Chem. 2018; 26(20):5397-5407 [PubMed] Related Publications
Histone acetyltransferases (HATs) relieve transcriptional repression by preferentially acetylation of ε-amino group of lysine residues on histones. Dysregulation of HATs is strongly correlated with etiology of several diseases especially cancer, thus highlighting the utmost significance of the development of small molecule inhibitors against this potential therapeutic target. In the present study, through virtual screening and iterative optimization, we identified DCH36_06 as a bona fide, potent p300/CBP inhibitor. DCH36_06 mediated p300/CBP inhibition leading to hypoacetylation on H3K18 in leukemic cells. The suppression of p300/CBP activity retarded cell proliferation in several leukemic cell lines. In addition, DCH36_06 arrested cell cycle at G1 phase and induced apoptosis via activation of capase3, caspase9 and PARP that elucidated the molecular mechanism of its anti-proliferation activity. In transcriptome analysis, DCH36_06 altered downstream gene expression and apoptotic pathways-related genes verified by real-time PCR. Importantly, DCH36_06 blocked the leukemic xenograft growth in mice supporting its potential for in vivo use that underlies the therapeutic potential for p300/CBP inhibitors in clinical translation. Taken together, our findings suggest that DCH36_06 may serve as a qualified chemical tool to decode the acetylome code and open up new opportunities for clinical intervention.

Shin SH, Lee GY, Lee M, et al.
Aberrant expression of CITED2 promotes prostate cancer metastasis by activating the nucleolin-AKT pathway.
Nat Commun. 2018; 9(1):4113 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Despite many efforts to develop hormone therapy and chemotherapy, no effective strategy to suppress prostate cancer metastasis has been established because the metastasis is not well understood. We here investigate a role of CBP/p300-interacting transactivator with E/D-rich carboxy-terminal domain-2 (CITED2) in prostate cancer metastasis. CITED2 is highly expressed in metastatic prostate cancer, and its expression is correlated with poor survival. The CITED2 gene is highly activated by ETS-related gene that is overexpressed due to chromosomal translocation. CITED2 acts as a molecular chaperone to guide PRMT5 and p300 to nucleolin, thereby activating nucleolin. Informatics and experimental data suggest that the CITED2-nucleolin axis is involved in prostate cancer metastasis. This axis stimulates cell migration through the epithelial-mesenchymal transition and promotes cancer metastasis in a xenograft mouse model. Our results suggest that CITED2 plays a metastasis-promoting role in prostate cancer and thus could be a target for preventing prostate cancer metastasis.

Zhao H, Yang Q, Hu Y, Zhang J
Antitumor effects and mechanisms of olaparib in combination with carboplatin and BKM120 on human triple‑negative breast cancer cells.
Oncol Rep. 2018; 40(6):3223-3234 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Triple‑negative breast cancer (TNBC) refers to a heterogeneous group of tumors, for which there is currently a lack of targeted therapies. Poly(ADP‑ribose) polymerase (PARP) inhibitors, phosphatidylinositol 3‑kinase (PI3K) inhibitors and carboplatin (CBP) have demonstrated sufficient efficacy and safety for their use as individual drugs for the treatment of TNBC; however, their effects on TNBC when used as a combination have not been investigated. The primary objectives of the present study were to determine the effects of a combination of CBP, olaparib and NVP‑BKM120 (BKM120), and to investigate the mechanism underlying their effects on TNBC cells. The drug combination was cytotoxic to TNBC cells, both with regards to short‑term and long‑term sensitivity, as determined using colony forming assays, and they exerted strong synergistic effects on MDA‑MB‑231 and CAL51 cell lines. All drugs affected cell cycle progression, and western blotting and immunofluorescence indicated that the the drug combination exerted its cytotoxicity via DNA damage, enhancing non‑homologous end joining repair and inhibiting homologous recombination repair. These data provide a strong rationale to explore the therapeutic use of olaparib in combination with CBP and BKM120 in animal models, and later in clinical trials on patients with TNBC.

Huang X, Yan J, Zhang M, et al.
Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors.
Cell. 2018; 175(1):186-199.e19 [PubMed] Related Publications
Mutations or aberrant upregulation of EZH2 occur frequently in human cancers, yet clinical benefits of EZH2 inhibitor (EZH2i) remain unsatisfactory and limited to certain hematological malignancies. We profile global posttranslational histone modification changes across a large panel of cancer cell lines with various sensitivities to EZH2i. We report here oncogenic transcriptional reprogramming mediated by MLL1's interaction with the p300/CBP complex, which directs H3K27me loss to reciprocal H3K27ac gain and restricts EZH2i response. Concurrent inhibition of H3K27me and H3K27ac results in transcriptional repression and MAPK pathway dependency in cancer subsets. In preclinical models encompassing a broad spectrum of EZH2-aberrant solid tumors, a combination of EZH2 and BRD4 inhibitors, or a triple-combination including MAPK inhibition display robust efficacy with very tolerable toxicity. Our results suggest an attractive precision treatment strategy for EZH2-aberrant tumors on the basis of tumor-intrinsic MLL1 expression and concurrent inhibition of epigenetic crosstalk and feedback MAPK activation.

Liu L, Yang Y, Liu S, et al.
EGF-induced nuclear localization of SHCBP1 activates β-catenin signaling and promotes cancer progression.
Oncogene. 2019; 38(5):747-764 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Aberrant activation of EGFR represents a common event in non-small cell lung carcinoma (NSCLC) and activates various downstream signaling pathways. While EGFR activation of β-catenin signaling was previously reported, the mediating mechanism remains unclear. Our current study found that EGFR activation in NSCLC cells releases SHC-binging protein 1 (SHCBP1) from SHC adaptor protein 1 (SHC1), which subsequently translocates into the nucleus and directly promotes the transactivating activity of β-catenin, consequently resulting in development of NSCLC cell stemness and malignant progression. Furthermore, SHCBP1 promotes β-catenin activity through enhancing the CBP/β-catenin interaction, and most interestingly, a candidate drug that blocks the CBP/β-catenin binding effectively abrogates the aforementioned biological effects of SHCBP1. Clinically, SHCBP1 level in NSCLC tumors was found to inversely correlate with patient survival. Together, our study establishes a novel convergence between EGFR and β-catenin pathways and highlights a potential significance of SHCBP1 as a prognostic biomarker and a therapeutic target.

Dong H, Wang W, Mo S, et al.
SP1-induced lncRNA AGAP2-AS1 expression promotes chemoresistance of breast cancer by epigenetic regulation of MyD88.
J Exp Clin Cancer Res. 2018; 37(1):202 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
BACKGROUND: Resistance to trastuzumab has become a leading cause of mortality in breast cancer patients and is one of the major obstacles for improving the clinical outcome. Cell behavior can be modulated by long non-coding RNAs (lncRNAs), but the contribution of lncRNAs in trastuzumab resistance to breast cancer is largely unknown. To this end, the involvement and regulatory function of lncRNA AGAP2-AS1 in human breast cancer are yet to be investigated.
METHODS: Trastuzumab-resistant SKBR-3 and BT474 cells were obtained by continuous culture with 5 mg/mL trastuzumab for 6 months. RT-qPCR assay was used to determine the expression of AGAP2-AS1 in tissues and cells. RNA fluorescence in situ hybridization was used to investigate the subcellular location of AGAP2-AS1 in breast cancer cells. Bioinformatic analysis, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), western blotting, and immunofluorescence were carried out to verify the regulatory interaction of AGAP2-AS1, CREB-binding protein (CBP), and MyD88. In addition, a series of in vitro assays and a xenograft tumor model were used to analyze the functions of AGAP2-AS1 in breast cancer cells.
RESULTS: AGAP2-AS1 was upregulated and transcriptionally induced by SP1 in breast cancer. Overexpression of AGAP2-AS1 promoted cell growth, suppressed apoptosis, and caused trastuzumab resistance, whereas knockdown of AGAP2-AS1 showed an opposite effect. MyD88 was identified as a downstream target of AGAP2-AS1 and mediated the AGAP2-AS1-induced oncogenic effects. Mechanistically, the RIP assay revealed that AGAP2-AS1 could bind to CBP, a transcriptional co-activator. ChIP assays showed that AGAP2-AS1-bound CBP increased the enrichment of H3K27ac at the promoter region of MyD88, thus resulting in the upregulation of MyD88. Gain- and loss-of-function assays confirmed that the NF-κB pathway was activated by MyD88 and AGAP2-AS1. Furthermore, high AGAP2-AS1 expression was associated with poor clinical response to trastuzumab therapy in breast cancer patients.
CONCLUSION: AGAP2-AS1 could promote breast cancer growth and trastuzumab resistance by activating the NF-κB signaling pathway and upregulating MyD88 expression. Therefore, AGAP2-AS1 may serve as a novel biomarker for prognosis and act as a therapeutic target for the trastuzumab treatment.

Zakaria C, Sean P, Hoang HD, et al.
Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis.
PLoS Pathog. 2018; 14(8):e1007264 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Herpes Simplex Virus 1 (HSV1) is amongst the most clinically advanced oncolytic virus platforms. However, efficient and sustained viral replication within tumours is limiting. Rapamycin can stimulate HSV1 replication in cancer cells, but active-site dual mTORC1 and mTORC2 (mammalian target of rapamycin complex 1 and 2) inhibitors (asTORi) were shown to suppress the virus in normal cells. Surprisingly, using the infected cell protein 0 (ICP0)-deleted HSV1 (HSV1-dICP0), we found that asTORi markedly augment infection in cancer cells and a mouse mammary cancer xenograft. Mechanistically, asTORi repressed mRNA translation in normal cells, resulting in defective antiviral response but also inhibition of HSV1-dICP0 replication. asTORi also reduced antiviral response in cancer cells, however in contrast to normal cells, transformed cells and cells transduced to elevate the expression of eukaryotic initiation factor 4E (eIF4E) or to silence the repressors eIF4E binding proteins (4E-BPs), selectively maintained HSV1-dICP0 protein synthesis during asTORi treatment, ultimately supporting increased viral replication. Our data show that altered eIF4E/4E-BPs expression can act to promote HSV1-dICP0 infection under prolonged mTOR inhibition. Thus, pharmacoviral combination of asTORi and HSV1 can target cancer cells displaying dysregulated eIF4E/4E-BPs axis.

Dong QF, Yan ZF, Li PQ, et al.
Inhibition of eIF4F complex loading inhibits the survival of malignant glioma.
Oncol Rep. 2018; 40(4):2399-2407 [PubMed] Related Publications
The eukaryotic initiation factor (eIF)4E‑binding proteins (4E‑BPs) regulate cap‑dependent protein translation and control the assembly of the eIF4F complex. In the present study, a phosphorylation‑deficient truncated 4E‑BP2 (eIF4FD) was constructed into the eukaryotic expression vector pSecTag2, and the in vitro and in vivo effects on malignant glioma survival were determined through inhibiting eIF4F complex assembly. Cell cycle distribution analysis and TUNEL staining show that overexpression of eIF4FD suppressed cell proliferation and induced apoptosis in U251 cells. Western blotting showed that the cell cycle‑related genes cyclin D1 and C‑myc, and anti‑apoptotic genes B‑cell lymphoma 2 (Bcl‑2), Bcl‑extra large and survivin were reduced following the overexpression of eIF4FD. Furthermore, eIF4FD suppressed glioma vascularization via reductions in the expression of β‑catenin and vascular endothelial growth factor. In the orthotopic xenograft model, the stable expression of eIF4FD in U251 cells attenuated cell growth and increased the rate of apoptosis. Accordingly, pSecTag2‑PTD‑eIF4FD injection via the tail vein of mice also lead to cell growth inhibition and the induction of apoptosis. Therefore, the study showed that phosphorylation‑deficient truncated 4E‑BP2 efficiently inhibited eIF4E and prevented the formation of the eIF4F complex, which further contributed to the inhibition of cell proliferation and vascularization, and the induction of apoptosis. Therefore, the 4E‑BP2‑based phosphorylation‑deficient truncation designed in the present study may represent a novel approach for the targeted therapy of human malignant glioma though inhibition of the translation initiation complex.

Kartha VK, Alamoud KA, Sadykov K, et al.
Functional and genomic analyses reveal therapeutic potential of targeting β-catenin/CBP activity in head and neck cancer.
Genome Med. 2018; 10(1):54 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy characterized by tumor heterogeneity, locoregional metastases, and resistance to existing treatments. Although a number of genomic and molecular alterations associated with HNSCC have been identified, they have had limited impact on the clinical management of this disease. To date, few targeted therapies are available for HNSCC, and only a small fraction of patients have benefited from these treatments. A frequent feature of HNSCC is the inappropriate activation of β-catenin that has been implicated in cell survival and in the maintenance and expansion of stem cell-like populations, thought to be the underlying cause of tumor recurrence and resistance to treatment. However, the therapeutic value of targeting β-catenin activity in HNSCC has not been explored.
METHODS: We utilized a combination of computational and experimental profiling approaches to examine the effects of blocking the interaction between β-catenin and cAMP-responsive element binding (CREB)-binding protein (CBP) using the small molecule inhibitor ICG-001. We generated and annotated in vitro treatment gene expression signatures of HNSCC cells, derived from human oral squamous cell carcinomas (OSCCs), using microarrays. We validated the anti-tumorigenic activity of ICG-001 in vivo using SCC-derived tumor xenografts in murine models, as well as embryonic zebrafish-based screens of sorted stem cell-like subpopulations. Additionally, ICG-001-inhibition signatures were overlaid with RNA-sequencing data from The Cancer Genome Atlas (TCGA) for human OSCCs to evaluate its association with tumor progression and prognosis.
RESULTS: ICG-001 inhibited HNSCC cell proliferation and tumor growth in cellular and murine models, respectively, while promoting intercellular adhesion and loss of invasive phenotypes. Furthermore, ICG-001 preferentially targeted the ability of subpopulations of stem-like cells to establish metastatic tumors in zebrafish. Significantly, interrogation of the ICG-001 inhibition-associated gene expression signature in the TCGA OSCC human cohort indicated that the targeted β-catenin/CBP transcriptional activity tracked with tumor status, advanced tumor grade, and poor overall patient survival.
CONCLUSIONS: Collectively, our results identify β-catenin/CBP interaction as a novel target for anti-HNSCC therapy and provide evidence that derivatives of ICG-001 with enhanced inhibitory activity may serve as an effective strategy to interfere with aggressive features of HNSCC.

Okonkwo A, Mitra J, Johnson GS, et al.
Heterocyclic Analogs of Sulforaphane Trigger DNA Damage and Impede DNA Repair in Colon Cancer Cells: Interplay of HATs and HDACs.
Mol Nutr Food Res. 2018; 62(18):e1800228 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
SCOPE: DNA repair inhibitors have broad clinical applications in tumor types with DNA repair defects, including colorectal cancer (CRC). Structural analogs of the anticancer agent sulforaphane (SFN) were investigated as modifiers of histone deacetylase (HDAC) and histone acetyltransferase (HAT) activity, and for effects on DNA damage/repair pertinent to human CRC.
METHODS AND RESULTS: In the polyposis in rat colon (Pirc) model, single oral administration of SFN and structurally related long-chain isothiocyanates (ITCs) decreased histone deacetylase 3 (HDAC3) expression and increased pH2AX levels markedly in adenomatous colon polyps, extending prior observations on HDAC3 inhibition/turnover in cell-based assays. Colon cancer cells at a high initial plating density had diminished cytotoxicity from SFN, whereas novel tetrazole-containing heterocyclic analogs of SFN retained their efficacy. The potent SFN analogs triggered DNA damage, cell cycle arrest, apoptosis, and loss of a key DNA repair regulator, C-terminal binding protein (CtBP) interacting protein (CtIP). These SFN analogs also altered HAT/HDAC activities and histone acetylation status, lowered the expression of HDAC3, P300/CBP-associated factor (PCAF) and lysine acetyltransferase 2A (KAT2A/GCN5), and attenuated homologous recombination (HR)/non-homologous end joining (NHEJ) repair activities in colon cancer cells.
CONCLUSION: Novel tetrazole-containing heterocyclic analogs of SFN provide a new avenue for chemosensitization in colon cancer cells via modulation of HAT/HDAC activities and associated DNA damage/repair signaling pathways.

Ren YM, Duan YH, Sun YB, et al.
Exploring the key genes and pathways of side population cells in human osteosarcoma using gene expression array analysis.
J Orthop Surg Res. 2018; 13(1):153 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
BACKGROUND: Human osteosarcoma (OS) is one of the most common primary bone sarcoma, because of early metastasis and few treatment strategies. It has been reported that the tumorigenicity and self-renewal capacity of side population (SP) cells play roles in human OS via regulating of target genes. This study aims to complement the differentially expressed genes (DEGs) that regulated between the SP cells and the non-SP cells from primary human OS and identify their functions and molecular pathways associated with OS.
METHODS: The gene expression profile GSE63390 was downloaded, and bioinformatics analysis was made.
RESULTS: One hundred forty-one DEGs totally were identified. Among them, 72 DEGs (51.06%) were overexpressed, and the remaining 69 DEGs (48.94%) were underexpressed. Gene ontology (GO) and pathway enrichment analysis of target genes were performed. We furthermore identified some relevant core genes using gene-gene interaction network analysis such as EIF4E, FAU, HSPD1, IL-6, and KISS1, which may have a relationship with the development process of OS. We also discovered that EIF4E/mTOR signaling pathway could be a potential research target for therapy and tumorigenesis of OS.
CONCLUSION: This analysis provides a comprehensive understanding of the roles of DEGs coming from SP cells in the development of OS. However, these predictions need further experimental validation in future studies.

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