HES1

Gene Summary

Gene:HES1; hes family bHLH transcription factor 1
Aliases: HHL, HRY, HES-1, bHLHb39
Location:3q28-q29
Summary:This protein belongs to the basic helix-loop-helix family of transcription factors. It is a transcriptional repressor of genes that require a bHLH protein for their transcription. The protein has a particular type of basic domain that contains a helix interrupting protein that binds to the N-box rather than the canonical E-box. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:transcription factor HES-1
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

What does this gene/protein do?
Show (77)
Pathways:What pathways are this gene/protein implicaed in?
Show (3)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 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.

  • Amyloid Precursor Protein Secretases
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Down-Regulation
  • Protease Inhibitors
  • Cell Movement
  • Liver Cancer
  • Cancer Stem Cells
  • Messenger RNA
  • Basic Helix-Loop-Helix Transcription Factors
  • Western Blotting
  • siRNA
  • Calcium-Binding Proteins
  • Promoter Regions
  • Cancer Gene Expression Regulation
  • Gene Expression
  • Translocation
  • Signal Transduction
  • DNA-Binding Proteins
  • Thiadiazoles
  • Cell Differentiation
  • Lung Cancer
  • Childhood Cancer
  • Antineoplastic Agents
  • NOTCH1 Receptor
  • Brain Tumours
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
  • Cell Survival
  • Repressor Proteins
  • Homeodomain Proteins
  • Mutation
  • Gene Expression Profiling
  • Chromosome 3
  • Myelodysplastic Syndromes
  • Brain Tumours
  • Immunohistochemistry
  • Transfection
  • Apoptosis
  • Cell Proliferation
  • Cell Cycle Proteins
  • Structure-Activity Relationship
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: HES1 (cancer-related)

Gao XJ, Liu JW, Zhang QG, et al.
Nobiletin inhibited hypoxia-induced epithelial-mesenchymal transition of lung cancer cells by inactivating of Notch-1 signaling and switching on miR-200b.
Pharmazie. 2015; 70(4):256-62 [PubMed] Related Publications
Epithelial-mesenchymal transition (EMT) is an early step in the process of tumor metastasis. It is well known that tumor microenvironment affects malignancy in various carcinomas; in particular, that hypoxia induces EMT. Deregulated notch signaling also contributes a lot to the development of EMT in lung cancer. In this study, we investigated the use of Notch-1-inhibiting compound as novel therapeutic candidates to regulate hypoxia-induced EMT in lung cancer cells. According to previous screening, nobiletin was selected as a Notch-1 inhibitor. Hypoxia-induced EMT was characteristic of increased N-cadherin & vimentin expressions and decreased E-cadherin expressions. Treatment with nobiletin notably attenuated hypoxia-induced EMT, invasion and migration in H1299 cells, accompanied with reduced Notch-1, Jagged1/2 expressions and its downstream genes Hey-1 and Hes-1. Nobiletin treatment also promoted tumorsuppressive miR-200b level. Moreover, notch-1 siRNA prevented hypoxia-mediated cell migration and decreased Twist1, Snail1, and ZEB1/2 expressions, which are key EMT markers. Re-expression of miR-200b blocked hypoxia-induced EMT and cell invasion. Our findings suggest that downregulation of Notch-1 and reexpression of miR-200b by nobiletin might be a novel remedy for the therapy of lung cancer.

Wang Y, Wu X, Ou L, et al.
PLCε knockdown inhibits prostate cancer cell proliferation via suppression of Notch signalling and nuclear translocation of the androgen receptor.
Cancer Lett. 2015; 362(1):61-9 [PubMed] Related Publications
Phospholipase Cε (PLCε), a key regulator of diverse cellular functions, has been implicated in various malignancies. Indeed, PLCε functions include cell proliferation, apoptosis and malignant transformation. Here, we show that PLCε expression is elevated in prostate cancer (PCa) tissues compared to benign prostate tissues. Furthermore, PLCε depletion using an adenovirally delivered shRNA significantly decreased cell growth and colony formation, arresting the PC3 and LNCaP cell lines in the S phase of the cell cycle. We also observed that PLCε was significantly correlated with Notch1 and androgen receptor (AR). Additionally, we demonstrate that the activation of both the Notch and AR signalling pathways is involved in PLCε-mediated oncogenic effects in PCa. Our findings suggest that PLCε is a putative oncogene and prognostic marker, potentially representing a novel therapeutic target for PCa.

Schnell SA, Ambesi-Impiombato A, Sanchez-Martin M, et al.
Therapeutic targeting of HES1 transcriptional programs in T-ALL.
Blood. 2015; 125(18):2806-14 [PubMed] Article available free on PMC after 30/04/2016 Related Publications
Oncogenic activation of NOTCH1 signaling plays a central role in the pathogenesis of T-cell acute lymphoblastic leukemia, with mutations on this signaling pathway affecting more than 60% of patients at diagnosis. However, the transcriptional regulatory circuitries driving T-cell transformation downstream of NOTCH1 remain incompletely understood. Here we identify Hairy and Enhancer of Split 1 (HES1), a transcriptional repressor controlled by NOTCH1, as a critical mediator of NOTCH1-induced leukemogenesis strictly required for tumor cell survival. Mechanistically, we demonstrate that HES1 directly downregulates the expression of BBC3, the gene encoding the PUMA BH3-only proapoptotic factor in T-cell acute lymphoblastic leukemia. Finally, we identify perhexiline, a small-molecule inhibitor of mitochondrial carnitine palmitoyltransferase-1, as a HES1-signature antagonist drug with robust antileukemic activity against NOTCH1-induced leukemias in vitro and in vivo.

Yuan R, Ke J, Sun L, et al.
HES1 promotes metastasis and predicts poor survival in patients with colorectal cancer.
Clin Exp Metastasis. 2015; 32(2):169-79 [PubMed] Related Publications
Hairy enhancer of split-1 (HES1) is a transcriptional target of the Notch pathway, and a high level of HES1 is regarded as a marker of activated Notch. The aim of the study was to investigate the role of HES1 in colorectal cancer progression. We used tissue microarrays to analyze the expression and clinical significance of HES1 in 320 colorectal cancer samples. Stable overexpression and knockdown of HES1 were established in three colorectal cancer cell (CRC) lines (RKO, HCT8 and LOVO). We investigated the differentially expressed genes and enriched pathways in HES1 overexpressing CRC cells by gene expression profiling. Also, the role of HES1 in invasion and migration were examined in vitro and in vivo. We found that high expression of HES1 was significantly correlated with distal metastasis (P = 0.037) at diagnosis, and HES1 could serve as an unfavorable prognostic factor for colorectal cancer patients (P = 0.034). Gene expression profiling and pathway enrichment analysis revealed that HES1 was related to cellular adherens junction loss. In addition, we showed that HES1 overexpression lead to depressed E-cadherin, and elevated N-cadherin, vimentin and Twist-1 levels. Functionally, HES1 enhanced invasiveness and metastasis of CRC cells. HES1 promotes cancer metastasis via inducing epithelial mesenchymal transition and serves as a poor prognosis factor of colorectal cancer patients.

Lv Q, Shen R, Wang J
RBPJ inhibition impairs the growth of lung cancer.
Tumour Biol. 2015; 36(5):3751-6 [PubMed] Related Publications
The exact effects of the modulation of Notch signaling pathway on cell growth have been shown to depend on tumor cell type. Recombination signal-binding protein Jκ (RBPJ) is a key transcription factor downstream of receptor activation in Notch signaling pathway. Here, we evaluated the effects of RBPJ inhibition on the growth of lung cancer cells. We found that a short hairpin interfering RNA (shRNA) for RBPJ efficiently inhibited RBPJ expression in lung cancer cells, resulting in a significant decrease in the cell growth. Further analyses showed that RBPJ inhibition altered the levels of its downstream targets, including p21, p27, CDK2, Hes1, Bcl-2, and SKP2, to prevent the cells from growing. Our data thus suggest that shRNA intervention of RBPJ expression could be a promising therapeutic approach for treating human lung cancer.

Brandt WD, Schreck KC, Bar EE, et al.
Notch signaling activation in pediatric low-grade astrocytoma.
J Neuropathol Exp Neurol. 2015; 74(2):121-31 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Pilocytic astrocytoma (PA) is the most common primary brain tumor in children; various signaling pathways have been implicated in its biology. The Notch signaling pathway has been found to play a role in the development, stem cell biology, and pathogenesis of several cancers, but its role in PA has not been investigated. We studied alterations in Notch signaling components in tumor tissue from 18 patients with PA and 4 with other low-grade astrocytomas to identify much needed therapeutic targets. We found that Notch pathway members were overexpressed at the mRNA (NOTCH1, NOTCH2, HEY1, HEY2) and protein (HES1) levels in PAs at various anatomic sites compared with non-neoplastic brain samples. These changes were not associated with specific BRAF alterations. Inhibiting the Notch pathway in the pediatric low-grade astrocytoma cell lines Res186 and Res259 using either RNA interference or a γ-secretase inhibitor resulted in variable, but significant, reduction in cell growth and migration. This study suggests a potential role for Notch signaling in pediatric low-grade astrocytoma tumorigenesis and that Notch signaling may be a viable pathway therapeutic target.

Wang H, Yang Z, Liu C, et al.
RBP-J-interacting and tubulin-associated protein induces apoptosis and cell cycle arrest in human hepatocellular carcinoma by activating the p53-Fbxw7 pathway.
Biochem Biophys Res Commun. 2014; 454(1):71-7 [PubMed] Related Publications
Aberrant Notch signaling is observed in human hepatocellular carcinoma (HCC) and has been associated with the modulation of cell growth. However, the role of Notch signaling in HCC and its underlying mechanism remain elusive. RBP-J-interacting and tubulin-associated (RITA) mediates the nuclear export of RBP-J to tubulin fibers and downregulates Notch-mediated transcription. In this study, we found that RITA overexpression increased protein expression of p53 and Fbxw7 and downregulated the expression of cyclin D1, cyclin E, CDK2, Hes-1 and NF-κB p65. These changes led to growth inhibition and induced G0/G1 cell cycle arrest and apoptosis in SMMC7721 and HepG2 cells. Our findings indicate that RITA exerts tumor-suppressive effects in hepatocarcinogenesis through induction of G0/G1 cell cycle arrest and apoptosis and suggest a therapeutic application of RITA in HCC.

Tang Y, Hu C, Yang H, et al.
Rnd3 regulates lung cancer cell proliferation through notch signaling.
PLoS One. 2014; 9(11):e111897 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Rnd3/RhoE is a small Rho GTPase involved in the regulation of different cell behaviors. Dysregulation of Rnd3 has been linked to tumorigenesis and metastasis. Lung cancers are the leading cause of cancer-related death in the West and around the world. The expression of Rnd3 and its ectopic role in non-small cell lung cancer (NSCLC) remain to be explored. Here, we reported that Rnd3 was down-regulated in three NSCLC cell lines: H358, H520 and A549. The down-regulation of Rnd3 led to hyper-activation of Rho Kinase and Notch signaling. The reintroduction of Rnd3 or selective inhibition of Notch signaling, but not Rho Kinase signaling, blocked the proliferation of H358 and H520 cells. Mechanistically, Notch intracellular domain (NICD) protein abundance in H358 cells was regulated by Rnd3-mediated NICD proteasome degradation. Rnd3 regulated H358 and H520 cell proliferation through a Notch1/NICD/Hes1 signaling axis independent of Rho Kinase.

Yan B, Liu L, Zhao Y, et al.
Xiaotan Sanjie decoction attenuates tumor angiogenesis by manipulating Notch-1-regulated proliferation of gastric cancer stem-like cells.
World J Gastroenterol. 2014; 20(36):13105-18 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
AIM: To determine the underlying mechanisms of action and influence of Xiaotan Sanjie (XTSJ) decoction on gastric cancer stem-like cells (GCSCs).
METHODS: The gastric cancer cell line MKN-45 line was selected and sorted by FACS using the cancer stem cell marker CD44; the stemness of these cells was checked in our previous study. In an in vitro study, the expression of Notch-1, Hes1, Vascular endothelial growth factor (VEGF), and Ki-67 in both CD44-positive gastric cancer stem-like cells (GCSCs) and CD44-negative cells was measured by Western blot. The effect of XTSJ serum on cell viability and on the above markers was measured by MTT assay and Western blot, respectively. In an in vivo study, the ability to induce angiogenesis and maintenance of GCSCs in CD44-positive-MKN-45- and CD44-negative-engrafted mice were detected by immunohistochemical staining using markers for CD34 and CD44, respectively. The role of XTSJ decoction in regulating the expression of Notch-1, Hes1, VEGF and Ki-67 was measured by Western blot and real-time polymerase chain reaction.
RESULTS: CD44(+) GCSCs showed more cell proliferation and VEGF secretion than CD44-negative cells in vitro, which were accompanied by the high expression of Notch-1 and Hes1 and positively associated with tumor growth (GCSCs vs CD44-negative cells, 2.72 ± 0.25 vs 1.46 ± 0.16, P < 0.05) and microvessel density (MVD) (GCSCs vs CD44-negative cells, 8.15 ± 0.42 vs 3.83 ± 0.49, P < 0.001) in vivo. XTSJ decoction inhibited the viability of both cell types in a dose-dependent manner in vitro. Specifically, a significant difference in the medium- (82.87% ± 6.53%) and high-dose XTSJ groups (77.43% ± 7.34%) was detected at 24 h in the CD44(+) GCSCs group compared with the saline group (95.42% ± 5.76%) and the low-dose XTSJ group (90.74% ± 6.57%) (P < 0.05). However, the efficacy of XTSJ decoction was reduced in the CD44(-) groups; significant differences were only detected in the high-dose XTSJ group at 48 h (78.57% ± 6.94%) and 72 h (72.12% ± 7.68%) when compared with the other CD44- groups (P < 0.05). Notably, these differences were highly consistent with the Notch-1, Hes1, VEGF and Ki-67 expression in these cells. Similarly, in vivo, XTSJ decoction inhibited tumor growth in a dose-dependent manner. A significant difference was observed in the medium- (1.76 ± 0.15) and high-dose XTSJ (1.33 ± 0.081) groups compared with the GCSCs control group (2.72 ± 0.25) and the low-dose XTSJ group (2.51 ± 0.25) (P < 0.05). We also detected a remarkable decrease of MVD in the medium- (7.10 ± 0.60) and high-dose XTSJ (5.99 ± 0.47) groups compared with the GCSC control group (8.15 ± 0.42) and the low-dose XTSJ group (8.14 ± 0.46) (P < 0.05). Additionally, CD44 expression was decreased in these groups [medium- (4.43 ± 0.45) and high-dose XTSJ groups (3.56 ± 0.31) vs the GCSC control (5.96 ± 0.46) and low dose XTSJ groups (5.91 ± 0.38)] (P < 0.05). The significant differences in Notch-1, Hes1, VEGF and Ki-67 expression highly mirrored the results of XTSJ decoction in inhibiting tumor growth, MVD and CD44 expression.
CONCLUSION: Notch-1 may play an important role in regulating the proliferation of GCSCs; XTSJ decoction could attenuate tumor angiogenesis, at least partially, by inhibiting Notch-1.

Kakar SS, Ratajczak MZ, Powell KS, et al.
Withaferin a alone and in combination with cisplatin suppresses growth and metastasis of ovarian cancer by targeting putative cancer stem cells.
PLoS One. 2014; 9(9):e107596 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Currently, the treatment for ovarian cancer entails cytoreductive surgery followed by chemotherapy, mainly, carboplatin combined with paclitaxel. Although this regimen is initially effective in a high percentage of cases, unfortunately within few months of initial treatment, tumor relapse occurs because of platinum-resistance. This is attributed to chemo-resistance of cancer stem cells (CSCs). Herein we show for the first time that withaferin A (WFA), a bioactive compound isolated from the plant Withania somnifera, when used alone or in combination with cisplatin (CIS) targets putative CSCs. Treatment of nude mice bearing orthotopic ovarian tumors generated by injecting human ovarian epithelial cancer cell line (A2780) with WFA and cisplatin (WFA) alone or in combination resulted in a 70 to 80% reduction in tumor growth and complete inhibition of metastasis to other organs compared to untreated controls. Histochemical and Western blot analysis of the tumors revealed that inclusion of WFA (2 mg/kg) resulted in a highly significant elimination of cells expressing CSC markers - CD44, CD24, CD34, CD117 and Oct4 and downregulation of Notch1, Hes1 and Hey1 genes. In contrast treatment of mice with CIS alone (6 mg/kg) had opposite effect on those cells. Increase in cells expressing CSC markers and Notch1 signaling pathway in tumors exposed to CIS may explain recurrence of cancer in patients treated with carboplatin and paclitaxel. Since, WFA alone or in combination with CIS eliminates putative CSCs, we conclude that WFA in combination with CIS may present more efficacious therapy for ovarian cancer.

Hirao Y, Matsuzaki H, Iwaki J, et al.
Glycoproteomics approach for identifying Glycobiomarker candidate molecules for tissue type classification of non-small cell lung carcinoma.
J Proteome Res. 2014; 13(11):4705-16 [PubMed] Related Publications
Histopathological classification of lung cancer has important implications in the application of clinical practice guidelines and the prediction of patient prognosis. Thus, we focused on discovering glycobiomarker candidates to classify the types of lung cancer tissue. First, we performed lectin microarray analysis of lung cancer tissue specimens and cell lines and identified Aleuria aurantia lectin (AAL), Hippeastrum hybrid lectin (HHL), and Concanavalia ensiformis agglutinin (ConA) as lectin probes specific to non-small cell lung carcinoma (NSCLC). LC-MS-based analysis was performed for the comprehensive identification of glycoproteins and N-linked glycosylation sites using lectin affinity capture of NSCLC-specific glycoforms of glycoproteins. This analysis identified 1092 AAL-bound glycoproteins (316 gene symbols) and 948 HHL/ConA-bound glycoproteins (279 gene symbols). The lectin microarray-assisted verification using 15 lung cancer cell lines revealed the NSCLC-specific expression of fibronectin. The glycosylation profiling of fibronectin indicated that the peanut agglutinin (PNA) signal appeared to differentiate two NSCLC types, adenocarcinoma and large cell carcinoma, whereas the protein expression level was similar between these types. Our glycoproteomics approach together with the concurrent use of an antibody and lectin is applicable to the quantitative and qualitative monitoring of variations in glycosylation of fibronectin specific to certain types of lung cancer tissue.

Kato T, Sakata-Yanagimoto M, Nishikii H, et al.
Hes1 suppresses acute myeloid leukemia development through FLT3 repression.
Leukemia. 2015; 29(3):576-85 [PubMed] Related Publications
In leukemogenesis, Notch signaling can be up and downregulated in a context-dependent manner. The transcription factor hairy and enhancer of split-1 (Hes1) is well-characterized as a downstream target of Notch signaling. Hes1 encodes a basic helix-loop-helix-type protein, and represses target gene expression. Here, we report that deletion of the Hes1 gene in mice promotes acute myeloid leukemia (AML) development induced by the MLL-AF9 fusion protein. We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity. FLT3 was consequently upregulated in MLL-AF9-expressing immortalized and leukemia cells with a Hes1- or RBPJ-null background. MLL-AF9-expressing Hes1-null AML cells showed enhanced proliferation and ERK phosphorylation following FLT3 ligand stimulation. FLT3 inhibition efficiently abrogated proliferation of MLL-AF9-induced Hes1-null AML cells. Furthermore, an agonistic anti-Notch2 antibody induced apoptosis of MLL-AF9-induced AML cells in a Hes1-wild type but not a Hes1-null background. We also accessed two independent databases containing messenger RNA (mRNA) expression profiles and found that the expression level of FLT3 mRNA was negatively correlated with those of HES1 in patient AML samples. These observations demonstrate that Hes1 mediates tumor suppressive roles of Notch signaling in AML development, probably by downregulating FLT3 expression.

Guerrero PA, Yin W, Camacho L, Marchetti D
Oncogenic role of Merlin/NF2 in glioblastoma.
Oncogene. 2015; 34(20):2621-30 [PubMed] Article available free on PMC after 14/11/2015 Related Publications
Glioblastoma is the most common and aggressive primary brain tumor in adults, with a poor prognosis because of its resistance to radiotherapy and chemotherapy. Merlin/NF2 (moesin-ezrin-radixin-like protein/neurofibromatosis type 2) is a tumor suppressor found to be mutated in most nervous system tumors; however, it is not mutated in glioblastomas. Merlin associates with several transmembrane receptors and intracellular proteins serving as an anchoring molecule. Additionally, it acts as a key component of cell motility. By selecting sub-populations of U251 glioblastoma cells, we observed that high expression of phosphorylated Merlin at serine 518 (S518-Merlin), NOTCH1 and epidermal growth factor receptor (EGFR) correlated with increased cell proliferation and tumorigenesis. These cells were defective in cell-contact inhibition with changes in Merlin phosphorylation directly affecting NOTCH1 and EGFR expression, as well as downstream targets HES1 (hairy and enhancer of split-1) and CCND1 (cyclin D1). Of note, we identified a function for S518-Merlin, which is distinct from what has been reported when the expression of Merlin is diminished in relation to EGFR and NOTCH1 expression, providing first-time evidence that demonstrates that the phosphorylation of S518-Merlin in glioblastoma promotes oncogenic properties that are not only the result of inactivation of the tumor suppressor role of Merlin but also an independent process implicating a Merlin-driven regulation of NOTCH1 and EGFR.

Tzeng TJ, Cao L, Fu Y, et al.
Methylseleninic acid sensitizes Notch3-activated OVCA429 ovarian cancer cells to carboplatin.
PLoS One. 2014; 9(7):e101664 [PubMed] Article available free on PMC after 14/11/2015 Related Publications
Ovarian cancer, the deadliest of gynecologic cancers, is usually not diagnosed until advanced stages. Although carboplatin has been popular for treating ovarian cancer for decades, patients eventually develop resistance to this platinum-containing drug. Expression of neurogenic locus notch homolog 3 (Notch3) is associated with chemoresistance and poor overall survival in ovarian cancer patients. Overexpression of NICD3 (the constitutively active form of Notch3) in OVCA429 ovarian cancer cells (OVCA429/NICD3) renders them resistance to carboplatin treatment compared to OVCA429/pCEG cells expressing an empty vector. We have previously shown that methylseleninic acid (MSeA) induces oxidative stress and activates ataxia-telangiectasia mutated and DNA-dependent protein kinase in cancer cells. Here we tested the hypothesis that MSeA and carboplatin exerted a synthetic lethal effect on OVCA429/NICD3 cells. Co-treatment with MSeA synergistically sensitized OVCA429/NICD3 but not OVCA429/pCEG cells to the killing by carboplatin. This synergism was associated with a cell cycle exit at the G2/M phase and the induction of NICD3 target gene HES1. Treatment of N-acetyl cysteine or inhibitors of the above two kinases did not directly impact on the synergism in OVCA429/NICD3 cells. Taken together, these results suggest that the efficacy of carboplatin in the treatment of high grade ovarian carcinoma can be enhanced by a combinational therapy with MSeA.

Capaccione KM, Hong X, Morgan KM, et al.
Sox9 mediates Notch1-induced mesenchymal features in lung adenocarcinoma.
Oncotarget. 2014; 5(11):3636-50 [PubMed] Article available free on PMC after 14/11/2015 Related Publications
Sox9 has gained increasing importance both functionally and as a prognostic factor in cancer. We demonstrate a functional role for Sox9 in inducing a mesenchymal phenotype in lung ADC. We show that Sox9 mRNA and protein are overexpressed in lung ADC, particularly those with KRAS mutations. Sox9 expression correlated with the Notch target gene Hes1, and numerous other Notch pathway components. We observed that Sox9 is a potent inducer of lung cancer cell motility and invasion, and a negative regulator of E-cadherin, a key protein that is lost during epithelial-mesenchymal transition (EMT). Moreover, we show that Notch1 signaling directly regulates Sox9 expression through a SOX9 promoter binding site, independently of the TGF-β pathway, and that Sox9 participates in Notch-1 induced cell motility, cell invasion, and loss of E-cadherin expression. Together, the results identify a new functional role for a Notch1-Sox9 signaling axis in lung ADC that may explain the correlation of Sox9 with tumor progression, higher tumor grade, and poor lung cancer survival. In addition to Notch and TGF-β, Sox9 also acts downstream of NF-κB, BMP, EGFR, and Wnt/β-catenin signaling. Thus, Sox9 could potentially act as a hub to mediate cross-talk among key oncogenic pathways in lung ADC. Targeting Sox9 expression or transcriptional activity could potentially reduce resistance to targeted therapy for lung ADC caused by pathway redundancy.

Fu W, Wang K, Zhao JL, et al.
FHL1C induces apoptosis in Notch1-dependent T-ALL cells through an interaction with RBP-J.
BMC Cancer. 2014; 14:463 [PubMed] Article available free on PMC after 14/11/2015 Related Publications
BACKGROUND: Aberrantly activated Notch signaling has been found in more than 50% of patients with T-cell acute lymphoblastic leukemia (T-ALL). Current strategies that employ γ-secretase inhibitors (GSIs) to target Notch activation have not been successful. Many limitations, such as non-Notch specificity, dose-limiting gastrointestinal toxicity and GSI resistance, have prompted an urgent need for more effective Notch signaling inhibitors for T-ALL treatment. Human four-and-a-half LIM domain protein 1C (FHL1C) (KyoT2 in mice) has been demonstrated to suppress Notch activation in vitro, suggesting that FHL1C may be new candidate target in T-ALL therapy. However, the role of FHL1C in T-ALL cells remained unclear.
METHODS: Using RT-PCR, we amplified full-length human FHL1C, and constructed full-length and various truncated forms of FHL1C. Using cell transfection, flow cytometry, transmission electron microscope, real-time RT-PCR, and Western blotting, we found that overexpression of FHL1C induced apoptosis of Jurkat cells. By using a reporter assay and Annexin-V staining, the minimal functional sequence of FHL1C inhibiting RBP-J-mediated Notch transactivation and inducing cell apoptosis was identified. Using real-time PCR and Western blotting, we explored the possible molecular mechanism of FHL1C-induced apoptosis. All data were statistically analyzed with the SPSS version 12.0 software.
RESULTS: In Jurkat cells derived from a Notch1-associated T-ALL cell line insensitive to GSI treatment, we observed that overexpression of FHL1C, which is down-regulated in T-ALL patients, strongly induced apoptosis. Furthermore, we verified that FHL1C-induced apoptosis depended on the RBP-J-binding motif at the C-terminus of FHL1C. Using various truncated forms of FHL1C, we found that the RBP-J-binding motif of FHL1C had almost the same effect as full-length FHL1C on the induction of apoptosis, suggesting that the minimal functional sequence in the RBP-J-binding motif of FHL1C might be a new drug candidate for T-ALL treatment. We also explored the molecular mechanism of FHL1C overexpression-induced apoptosis, which suppressed downstream target genes such as Hes1 and c-Myc and key signaling pathways such as PI3K/AKT and NF-κB of Notch signaling involved in T-ALL progression.
CONCLUSIONS: Our study has revealed that FHL1C overexpression induces Jurkat cell apoptosis. This finding may provide new insights in designing new Notch inhibitors based on FHL1C to treat T-ALL.

Liu W, Xu C, Wan H, et al.
MicroRNA-206 overexpression promotes apoptosis, induces cell cycle arrest and inhibits the migration of human hepatocellular carcinoma HepG2 cells.
Int J Mol Med. 2014; 34(2):420-8 [PubMed] Article available free on PMC after 14/11/2015 Related Publications
MicroRNA-206 (miR-206) is known to regulate cell proliferation and migration and is involved in various types of cancer. However, the role of miR-206 in human hepatocellular carcinoma (HHC) has not been previously reported. In the present study, the expression of Notch3 in HCC and adjacent non-neoplastic tissue was immunohistochemically assessed on formalin-fixed, paraffin-embedded sections. miR-206 mimics were transiently transfected into HepG2 cells using Lipofectamine™ 2000. Subsequently, we evaluated the role of miR-206 in cell proliferation, apoptosis, cell cycle arrest and migration by MTS assay, Hoechst 33342 staining, Annexin V-FITC/PI assay, flow cytometry and wound healing assay. Using quantitative reverse transcription polymerase chain reaction (qRT‑PCR) and western blot analysis, we detected the expression of Notch3, Bax, Bcl-2, Hes1, p57 and matrix metalloproteinase (MMP)-9 at the mRNA and protein level, respectively. In addition, we measured the expression of miR-206 at the mRNA level and that of caspase-3 at the protein level. After miR-206 was upregulated in HepG2 cells, Notch3, Hes1, Bcl-2 and MMP-9 were downregulated both at the mRNA and protein level, whereas p57 and Bax were upregulated. Cleaved caspase-3 protein expression was also markedly increased. Cell proliferation was significantly attenuated and apoptosis was markedly increased. Furthermore, miR-206 overexpression induced cell cycle arrest and inhibited the migration of HepG2 cells. Taken together, our results uggest that miR-206 is a potential regulator of apoptosis, the cell cycle and migration in HepG2 cells and that it has the potential for use in the targeted therapy of HCC and is a novel tumor suppressor.

Chao CH, Chang CC, Wu MJ, et al.
MicroRNA-205 signaling regulates mammary stem cell fate and tumorigenesis.
J Clin Invest. 2014; 124(7):3093-106 [PubMed] Article available free on PMC after 14/11/2015 Related Publications
Dysregulation of epigenetic controls is associated with tumorigenesis in response to microenvironmental stimuli; however, the regulatory pathways involved in epigenetic dysfunction are largely unclear. We have determined that a critical epigenetic regulator, microRNA-205 (miR-205), is repressed by the ligand jagged1, which is secreted from the tumor stroma to promote a cancer-associated stem cell phenotype. Knockdown of miR-205 in mammary epithelial cells promoted epithelial-mesenchymal transition (EMT), disrupted epithelial cell polarity, and enhanced symmetric division to expand the stem cell population. Furthermore, miR-205-deficient mice spontaneously developed mammary lesions, while activation of miR-205 markedly diminished breast cancer stemness. These data provide evidence that links tumor microenvironment and microRNA-dependent regulation to disruption of epithelial polarity and aberrant mammary stem cell division, which in turn leads to an expansion of stem cell population and tumorigenesis. This study elucidates an important role for miR-205 in the regulation of mammary stem cell fate, suggesting a potential therapeutic target for limiting breast cancer genesis.

Gao J, Azmi AS, Aboukameel A, et al.
Nuclear retention of Fbw7 by specific inhibitors of nuclear export leads to Notch1 degradation in pancreatic cancer.
Oncotarget. 2014; 5(11):3444-54 [PubMed] Article available free on PMC after 14/11/2015 Related Publications
Chromosome maintenance region 1 (CRM1) also called Exportin 1 (Xpo1), a protein found elevated in pancreatic ductal adenocarcinoma (PDAC), blocks tumor suppressor protein (TSP) function through constant nuclear export. Earlier we had shown that targeting CRM1 by our newly developed specific inhibitors of nuclear export (SINE) leads to inhibition of pancreatic cancer cell proliferation and tumor growth arrest. In this paper we define the mechanism of SINE action. Our lead SINE KPT-185 inhibits PDAC cell growth, cell migration, tumor invasion and induces apoptosis and G2-M cell cycle arrest in low nano molar range (IC50s~150 nM). Mechanistically we demonstrate that the activity of KPT-185 is associated with nuclear retention of Fbw7; which degrades nuclear Notch-1 leading to decreased tumor promoting markers such as C-Myc, Cyclin-D1, Hes1 and VEGF. The orally bioavailable SINE (KPT-251) showed potent anti-tumor activity in a Colo-357 PDAC xenografts model; residual tumor analysis showed activation of Fbw7 concomitant with attenuation of Notch1 and its downstream genes. These results suggest that the antitumor activity of KPT-185 is in part due to nuclear retention of Fbw7 and consequent Notch1 degradation. The new CRM1 inhibitors, therefore, hold strong potential and warrant further clinical investigations for PDAC.

Barøy T, Kresse SH, Skårn M, et al.
Reexpression of LSAMP inhibits tumor growth in a preclinical osteosarcoma model.
Mol Cancer. 2014; 13:93 [PubMed] Article available free on PMC after 14/11/2015 Related Publications
BACKGROUND: Osteosarcomas are the most common primary malignant tumors of bone, showing complex chromosomal rearrangements with multiple gains and losses. A frequent deletion within the chromosomal region 3q13.31 has been identified by us and others, and is mainly reported to be present in osteosarcomas. The purpose of the study was to further characterize the frequency and the extent of the deletion in an extended panel of osteosarcoma samples, and the expression level of the affected genes within the region. We have identified LSAMP as the target gene for the deletion, and have studied the functional implications of LSAMP-reexpression.
METHODS: LSAMP copy number, expression level and protein level were investigated by quantitative PCR and western blotting in an osteosarcoma panel. The expression of LSAMP was restored in an osteosarcoma cell line, and differences in proliferation rate, tumor formation, gene expression, migration rate, differentiation capabilities, cell cycle distribution and apoptosis were investigated by metabolic dyes, tumor formation in vivo, gene expression profiling, time-lapse photography, differentiation techniques and flow cytometry, respectively.
RESULTS: We found reduced copy number of LSAMP in 45/76 osteosarcoma samples, reduced expression level in 25/42 samples and protein expression in 9/42 samples. By restoring the expression of LSAMP in a cell line with a homozygous deletion of the gene, the proliferation rate in vitro was significantly reduced and tumor growth in vivo was significantly delayed. In response to reexpression of LSAMP, mRNA expression profiling revealed consistent upregulation of the genes hairy and enhancer of split 1 (HES1), cancer/testis antigen 2 (CTAG2) and kruppel-like factor 10 (KLF10).
CONCLUSIONS: The high frequency and the specificity of the deletion indicate that it is important for the development of osteosarcomas. The deletion targets the tumor suppressor LSAMP, and based on the functional evidence, the tumor suppressor function of LSAMP is most likely exerted by reducing the proliferation rate of the tumor cells, possibly by indirectly upregulating one or more of the genes HES1, CTAG2 or KLF10. To our knowledge, this study describes novel functions of LSAMP, a first step to understanding the functional role of this specific deletion in osteosarcomas.

Nakahara F, Kitaura J, Uchida T, et al.
Hes1 promotes blast crisis in chronic myelogenous leukemia through MMP-9 upregulation in leukemic cells.
Blood. 2014; 123(25):3932-42 [PubMed] Related Publications
High levels of HES1 expression are frequently found in BCR-ABL(+) chronic myelogenous leukemia in blast crisis (CML-BC). In mouse bone marrow transplantation (BMT) models, co-expression of BCR-ABL and Hes1 induces CML-BC-like disease; however, the underlying mechanism remained elusive. Here, based on gene expression analysis, we show that MMP-9 is upregulated by Hes1 in common myeloid progenitors (CMPs). Analysis of promoter activity demonstrated that Hes1 upregulated MMP-9 by activating NF-κB. Analysis of 20 samples from CML-BC patients showed that MMP-9 was highly expressed in three, with two exhibiting high levels of HES1 expression. Interestingly, MMP-9 deficiency impaired the cobblestone area-forming ability of CMPs expressing BCR-ABL and Hes1 that were in conjunction with a stromal cell layer. In addition, CMPs expressing BCR-ABL and Hes1 secreted MMP-9, promoting the release of soluble Kit-ligand (sKitL) from stromal cells, thereby enhancing proliferation of the leukemic cells. In accordance, mice transplanted with CMPs expressing BCR-ABL and Hes1 exhibited high levels of sKitL as well as MMP-9 in the serum. Importantly, MMP-9 deficiency impaired the development of CML-BC-like disease induced by BCR-ABL and Hes1 in mouse BMT models. The present results suggest that Hes1 promotes the development of CML-BC, partly through MMP-9 upregulation in leukemic cells.

De Salvo M, Raimondi L, Vella S, et al.
Hyper-activation of Notch3 amplifies the proliferative potential of rhabdomyosarcoma cells.
PLoS One. 2014; 9(5):e96238 [PubMed] Article available free on PMC after 14/11/2015 Related Publications
Rhabdomyosarcoma (RMS) is a pediatric myogenic-derived soft tissue sarcoma that includes two major histopathological subtypes: embryonal and alveolar. The majority of alveolar RMS expresses PAX3-FOXO1 fusion oncoprotein, associated with the worst prognosis. RMS cells show myogenic markers expression but are unable to terminally differentiate. The Notch signaling pathway is a master player during myogenesis, with Notch1 activation sustaining myoblast expansion and Notch3 activation inhibiting myoblast fusion and differentiation. Accordingly, Notch1 signaling is up-regulated and activated in embryonal RMS samples and supports the proliferation of tumor cells. However, it is unable to control their differentiation properties. We previously reported that Notch3 is activated in RMS cell lines, of both alveolar and embryonal subtype, and acts by inhibiting differentiation. Moreover, Notch3 depletion reduces PAX3-FOXO1 alveolar RMS tumor growth in vivo. However, whether Notch3 activation also sustains the proliferation of RMS cells remained unclear. To address this question, we forced the expression of the activated form of Notch3, Notch3IC, in the RH30 and RH41 PAX3-FOXO1-positive alveolar and in the RD embryonal RMS cell lines and studied the proliferation of these cells. We show that, in all three cell lines tested, Notch3IC over-expression stimulates in vitro cell proliferation and prevents the effects of pharmacological Notch inhibition. Furthermore, Notch3IC further increases RH30 cell growth in vivo. Interestingly, knockdown of Notch canonical ligands JAG1 or DLL1 in RMS cell lines decreases Notch3 activity and reduces cell proliferation. Finally, the expression of Notch3IC and its target gene HES1 correlates with that of the proliferative marker Ki67 in a small cohort of primary PAX-FOXO1 alveolar RMS samples. These results strongly suggest that high levels of Notch3 activation increase the proliferative potential of RMS cells.

Miao L, Xiong X, Lin Y, et al.
Down-regulation of FoxM1 leads to the inhibition of the epithelial-mesenchymal transition in gastric cancer cells.
Cancer Genet. 2014; 207(3):75-82 [PubMed] Related Publications
Emerging evidence suggests that FoxM1 may have a crucial role in the development and progression of human gastric cancer. Therefore, we sought to determine the role of FoxM1 in gastric cancer epithelial-mesenchymal transition (EMT). The down-regulation of FoxM1 expression by the transfection of cells with FoxM1 siRNA decreased cell migration, invasion, and proliferation. Moreover, the over-expression of FoxM1 promoted cell migration, invasion, and proliferation, which led to the acquisition of an EMT phenotype by up-regulating the protein expression of the mesenchymal cell markers ZEB1, ZEB2, and vimentin and by down-regulating the epithelial cell marker E-cadherin in gastric epithelial cells. More important, the depletion of FoxM1 levels in gastric cancer cells led to significant decreases in the NF-κB p65 subunit, cyclin D1, Hes-1, VEGF, and EpCAM protein levels. Real-time PCR examination showed that the down-regulation of FoxM1 expression significantly inhibited vimentin and N-cadherin expression compared to that in control cells. Most important, cells transfected with FoxM1 siRNA displayed an elongated/irregular fibroblastoid morphology and reduction of the vimentin expression. Our current study strongly suggests that FoxM1 signaling has important roles in tumor cell aggressiveness through the acquisition of the EMT phenotype in gastric cancer cells.

Zhang S, Chung WC, Wu G, et al.
Tumor-suppressive activity of Lunatic Fringe in prostate through differential modulation of Notch receptor activation.
Neoplasia. 2014; 16(2):158-67 [PubMed] Article available free on PMC after 14/11/2015 Related Publications
Elevated Notch ligand and receptor expression has been associated with aggressive forms of prostate cancer, suggesting a role for Notch signaling in regulation of prostate tumor initiation and progression. Here, we report a critical role for Lunatic Fringe (Lfng), which encodes an O-fucosylpeptide 3-ß-N-acetylglucosaminyltransferase known to modify epidermal growth factor repeats of Notch receptor proteins, in regulation of prostate epithelial differentiation and proliferation, as well as in prostate tumor suppression. Deletion of Lfng in mice caused altered Notch activation in the prostate, associated with elevated accumulation of Notch1, Notch2, and Notch4 intracellular domains, decreased levels of the putative Notch3 intracellular fragment, as well as increased expression of Hes1, Hes5, and Hey2. Loss of Lfng resulted in expansion of the basal layer, increased proliferation of both luminal and basal cells, and ultimately, prostatic intraepithelial neoplasia. The Lfng-null prostate showed down-regulation of prostatic tumor suppressor gene NKX3.1 and increased androgen receptor expression. Interestingly, expression of LFNG and NKX3.1 were positively correlated in publically available human prostate cancer data sets. Knockdown of LFNG in DU-145 prostate cancer cells led to expansion of CD44(+)CD24(-) and CD49f(+)CD24(-) stem/progenitor-like cell population associated with enhanced prostatosphere-forming capacity. Taken together, these data revealed a tumor-suppressive role for Lfng in the prostate through differential regulation of Notch signaling.

Fiaschetti G, Schroeder C, Castelletti D, et al.
NOTCH ligands JAG1 and JAG2 as critical pro-survival factors in childhood medulloblastoma.
Acta Neuropathol Commun. 2014; 2:39 [PubMed] Article available free on PMC after 14/11/2015 Related Publications
Medulloblastoma (MB), the most common pediatric malignant brain cancer, typically arises as pathological result of deregulated developmental pathways, including the NOTCH signaling cascade. Unlike the evidence supporting a role for NOTCH receptors in MB development, the pathological functions of NOTCH ligands remain largely unexplored. By examining the expression in large cohorts of MB primary tumors, and in established in vitro MB models, this research study demonstrates that MB cells bear abnormal levels of distinct NOTCH ligands. We explored the potential association between NOTCH ligands and the clinical outcome of MB patients, and investigated the rational of inhibiting NOTCH signaling by targeting specific ligands to ultimately provide therapeutic benefits in MB. The research revealed a significant over-expression of ligand JAG1 in the vast majority of MBs, and proved that JAG1 mediates pro-proliferative signals via activation of NOTCH2 receptor and induction of HES1 expression, thus representing an attractive therapeutic target. Furthermore, we could identify a clinically relevant association between ligand JAG2 and the oncogene MYC, specific for MYC-driven Group 3 MB cases. We describe for the first time a mechanistic link between the oncogene MYC and NOTCH pathway in MB, by identifying JAG2 as MYC target, and by showing that MB cells acquire induced expression of JAG2 through MYC-induced transcriptional activation. Finally, the positive correlation of MYC and JAG2 also with aggressive anaplastic tumors and highly metastatic MB stages suggested that high JAG2 expression may be useful as additional marker to identify aggressive MBs.

Cordeiro BM, Oliveira ID, Alves MT, et al.
SHH, WNT, and NOTCH pathways in medulloblastoma: when cancer stem cells maintain self-renewal and differentiation properties.
Childs Nerv Syst. 2014; 30(7):1165-72 [PubMed] Related Publications
PURPOSE: Infant medulloblastoma (MB) is a malignant neuroepithelial embryonal tumor of the cerebellum, believed to derive from precursor granule cells with stem or progenitor cells appearance, and caused by a change in expression profile of genes related to the development. This work aims to study the expression profile of these genes in MB tumors, correlating with clinicopathological characteristics.
METHODS: We quantified, by qPCR in 40 MB tumor samples, the expression of genes in HH (PTCH1, PTCH2, and GLI1), WNT (APC, CTNNB1, WIF1, and DKK2), and NOTCH pathways (NOTCH2 and HES1), which have a crucial role in development, and genes as MYCC, MYCN, and TERT, correlating this findings to patient's clinicopathological characteristics.
RESULTS: Considering the universal RNA as our control sample, and considering the median of gene expression in the control samples as our cutoff, we observed that HES1 gene showed decreased expression compared to control (p = 0.0059), but patients with HES1 overexpression were directly related to a shorter survival (p = 0.0165). Individuals with higher GLI1 gene expression had significant shorter survival (p = 0.0469), and high expression was prevalent in patients up to 5 years old (p = 0.0479). Patients showing high PTCH2 expression were related to worse survival (p = 0.0426), and it was correlated with GLI1 high expression (p = 0.0094). We also observed a concomitant overexpression of WIF1 and DKK2 genes in a subgroup of MB samples (n = 11, p = 0.0118).
CONCLUSIONS: Our results suggest the presence of activated developmental signaling pathways in MB, which are important for cell proliferation and maintenance, and that may be targeted for novel therapeutic options.

Alaña L, Sesé M, Cánovas V, et al.
Prostate tumor OVerexpressed-1 (PTOV1) down-regulates HES1 and HEY1 notch targets genes and promotes prostate cancer progression.
Mol Cancer. 2014; 13:74 [PubMed] Article available free on PMC after 14/11/2015 Related Publications
BACKGROUND: PTOV1 is an adaptor protein with functions in diverse processes, including gene transcription and protein translation, whose overexpression is associated with a higher proliferation index and tumor grade in prostate cancer (PC) and other neoplasms. Here we report its interaction with the Notch pathway and its involvement in PC progression.
METHODS: Stable PTOV1 knockdown or overexpression were performed by lentiviral transduction. Protein interactions were analyzed by co-immunoprecipitation, pull-down and/or immunofluorescence. Endogenous gene expression was analyzed by real time RT-PCR and/or Western blotting. Exogenous promoter activities were studied by luciferase assays. Gene promoter interactions were analyzed by chromatin immunoprecipitation assays (ChIP). In vivo studies were performed in the Drosophila melanogaster wing, the SCID-Beige mouse model, and human prostate cancer tissues and metastasis. The Excel package was used for statistical analysis.
RESULTS: Knockdown of PTOV1 in prostate epithelial cells and HaCaT skin keratinocytes caused the upregulation, and overexpression of PTOV1 the downregulation, of the Notch target genes HEY1 and HES1, suggesting that PTOV1 counteracts Notch signaling. Under conditions of inactive Notch signaling, endogenous PTOV1 associated with the HEY1 and HES1 promoters, together with components of the Notch repressor complex. Conversely, expression of active Notch1 provoked the dismissal of PTOV1 from these promoters. The antagonist role of PTOV1 on Notch activity was corroborated in the Drosophila melanogaster wing, where human PTOV1 exacerbated Notch deletion mutant phenotypes and suppressed the effects of constitutively active Notch. PTOV1 was required for optimal in vitro invasiveness and anchorage-independent growth of PC-3 cells, activities counteracted by Notch, and for their efficient growth and metastatic spread in vivo. In prostate tumors, the overexpression of PTOV1 was associated with decreased expression of HEY1 and HES1, and this correlation was significant in metastatic lesions.
CONCLUSIONS: High levels of the adaptor protein PTOV1 counteract the transcriptional activity of Notch. Our evidences link the pro-oncogenic and pro-metastatic effects of PTOV1 in prostate cancer to its inhibitory activity on Notch signaling and are supportive of a tumor suppressor role of Notch in prostate cancer progression.

Li L, Tan J, Zhang Y, et al.
DLK1 promotes lung cancer cell invasion through upregulation of MMP9 expression depending on Notch signaling.
PLoS One. 2014; 9(3):e91509 [PubMed] Article available free on PMC after 14/11/2015 Related Publications
The transmembrane and secreted protein delta-like 1 homolog (DLK1) belongs to the EGF-like family. It is widely accepted that DLK1 plays important roles in regulating cell differentiation, such as adipogenesis and osteogenesis. Aberrant expression of DLK1 has been found in various types of human cancers, including lung cancer. A previous study in this lab has revealed that DLK1 is associated with tumor invasion, although the mechanism is still unknown. To explore the potential effects that DLK1 might have on invasion, DLK1 was overexpressed or knocked down in the human lung cancer cell lines. The protein's influences on cell invasion were subsequently evaluated. A transwell assay showed that DLK1 overexpression significantly promoted cancer cell invasion. Western blotting and gelatin zymography analysis indicated that DLK1 could affect both matrix metalloproteinase-9 (MMP9) expression and its extracellular activity. An analysis of NOTCH1 and HES1 gene expression and Notch intracellular domain (NICD) nuclear translocation during DLK1 stimulation or depletion demonstrated that DLK1 could activate Notch signaling in lung cancer cells. Additionally, the elevated expression of MMP9 induced by DLK1 stimulation could be significantly decreased by inhibiting Notch signaling using γ-secretase inhibitor (GSI). The data presented in this study suggest that DLK1 can promote the invasion of lung cancer cells by upregulating MMP9 expression, which depends on Notch signaling.

Wang M, Ma X, Wang J, et al.
Pretreatment with the γ-secretase inhibitor DAPT sensitizes drug-resistant ovarian cancer cells to cisplatin by downregulation of Notch signaling.
Int J Oncol. 2014; 44(4):1401-9 [PubMed] Related Publications
Notch signaling is implicated in ovarian cancer tumorigenesis and inhibition of Notch signaling with γ-secretase inhibitor DAPT resulted in reduction of tumor cell viability and induction of apoptosis in ovarian cancer cells. This study investigated whether DAPT has the same effect on ovarian cancer cells that are resistant to cisplatin and the underlying molecular events. Ovarian cancer cell lines resistant to cisplatin were treated with DAPT, cisplatin or combination for cell viability MTT, flow cytometric cell cycle, ELISA apoptosis and colony formation assays. qRT-PCR and western blotting were used to detect gene expressions. We found that pretreatment of ovarian cancer cisplatin-resistant cell lines with DAPT for 24 h and then with cisplatin for 72 h showed a synergistic antitumor activity in these cell lines, while cisplatin treatment and then addition of DAPT just showed an additive or antagonistic effects on these cisplatin-resistant ovarian cancer cells. Moreover, pretreatment of ovarian cancer cell lines with DAPT and then with cisplatin also inhibited tumor cell colony formation capacity, arrested tumor cells at G2 phase of the cell cycle and induced apoptosis. The cell cycle and apoptosis-related genes, such as cyclin B1, Bcl-2 and caspase-3, were also modulated by the treatment. Pretreatment of ovarian cancer cell lines with DAPT and then with cisplatin downregulated Notch1 and Hes1 expression dose- and time-dependently. The current data demonstrate that DAPT pretreatment was able to sensitize cisplatin-resistant human ovarian cancer cells to cisplatin by downregulation of Notch signaling.

Qiu M, Bao W, Wang J, et al.
FOXA1 promotes tumor cell proliferation through AR involving the Notch pathway in endometrial cancer.
BMC Cancer. 2014; 14:78 [PubMed] Article available free on PMC after 14/11/2015 Related Publications
BACKGROUND: Increasing evidence suggests that forkhead box A1 (FOXA1) is frequently dysregulated in many types of human cancers. However, the exact function and mechanism of FOXA1 in human endometrial cancer (EC) remains unclear.
METHODS: FOXA1 expression, androgen receptor (AR) expression, and the relationships of these two markers with clinicopathological factors were determined by immunohistochemistry analysis. FOXA1 and AR were up-regulated by transient transfection with plasmids, and were down-regulated by transfection with siRNA or short hairpin RNA (shRNA). The effects of FOXA1 depletion and FOXA1 overexpression on AR-mediated transcription as well as Notch pathway and their impact on EC cell proliferation were examined by qRT-PCR, western blotting, co-immunoprecipitation, ChIP-PCR, MTT, colony-formation, and xenograft tumor-formation assays.
RESULTS: We found that the expression of FOXA1 and AR in ECs was significantly higher than that in a typical hyperplasia and normal tissues. FOXA1 expression was significantly correlated with AR expression in clinical tissues. High FOXA1 levels positively correlated with pathological grade and depth of myometrial invasion in EC. High AR levels also positively correlated with pathological grade in EC. Moreover, the expression of XBP1, MYC, ZBTB16, and UHRF1, which are downstream targets of AR, was promoted by FOXA1 up-regulation or inhibited by FOXA1 down-regulation. Co-immunoprecipitation showed that FOXA1 interacted with AR in EC cells. ChIP-PCR assays showed that FOXA1 and AR could directly bind to the promoter and enhancer regions upstream of MYC. Mechanistic investigation revealed that over-expression of Notch1 and Hes1 proteins by FOXA1 could be reversed by AR depletion. In addition, we showed that down-regulation of AR attenuated FOXA1-up-regulated cell proliferation. However, AR didn't influence the promotion effect of FOXA1 on cell migration and invasion. In vivo xenograft model, FOXA1 knockdown reduced the rate of tumor growth.
CONCLUSIONS: These results suggest that FOXA1 promotes cell proliferation by AR and activates Notch pathway. It indicated that FOXA1 and AR may serve as potential gene therapy in EC.

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