CREB1

Gene Summary

Gene:CREB1; cAMP responsive element binding protein 1
Aliases: CREB
Location:2q34
Summary:This gene encodes a transcription factor that is a member of the leucine zipper family of DNA binding proteins. This protein binds as a homodimer to the cAMP-responsive element, an octameric palindrome. The protein is phosphorylated by several protein kinases, and induces transcription of genes in response to hormonal stimulation of the cAMP pathway. Alternate splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:cyclic AMP-responsive element-binding protein 1
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

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

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 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.

  • Soft Tissue Cancers
  • Calmodulin-Binding Proteins
  • Apoptosis
  • Messenger RNA
  • Transcription
  • Cyclic AMP
  • CREB1
  • Base Sequence
  • Extracellular Signal-Regulated MAP Kinases
  • Cell Proliferation
  • Tumor Markers
  • Promoter Regions
  • Childhood Cancer
  • Cell Differentiation
  • Oncogene Fusion Proteins
  • RNA-Binding Proteins
  • Signal Transduction
  • Gene Expression Profiling
  • Prostate Cancer
  • Adolescents
  • FISH
  • Histiocytoma, Malignant Fibrous
  • Breast Cancer
  • Thigh
  • Phosphorylation
  • Cyclic AMP Response Element-Binding Protein
  • Molecular Sequence Data
  • DNA-Binding Proteins
  • siRNA
  • Chromosome 2
  • Soft Tissue Sarcoma
  • Clear Cell Sarcoma
  • Transcription Factors
  • Lung Cancer
  • MicroRNAs
  • Proteasome Endopeptidase Complex
  • Cancer Gene Expression Regulation
  • Immunohistochemistry
  • Up-Regulation
  • Neoplasm Proteins
  • Transcriptional Activation
  • Gene Rearrangement
Tag cloud generated 17 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: CREB1 (cancer-related)

Thway K, Fisher C
Angiomatoid fibrous histiocytoma: the current status of pathology and genetics.
Arch Pathol Lab Med. 2015; 139(5):674-82 [PubMed] Related Publications
CONTEXT: Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue neoplasm of intermediate biologic potential and uncertain differentiation, most often arising in the superficial extremities of children and young adults. While it has characteristic histologic features of nodular distributions of ovoid and spindle cells with blood-filled cystic cavities and a surrounding dense lymphoplasmacytic infiltrate, there is a significant morphologic spectrum, which coupled with its rarity and lack of specific immunoprofile can make diagnosis challenging. Angiomatoid fibrous histiocytoma is associated with 3 characteristic gene fusions, EWSR1-CREB1 and EWSR1-ATF1, which are also described in other neoplasms, and rarely FUS-ATF1. Angiomatoid fibrous histiocytoma is now recognized at an increasing number of sites and is known to display a variety of unusual histologic features.
OBJECTIVE: To review the current status of AFH, discussing putative etiology, histopathology with variant morphology and differential diagnosis, and current genetics, including overlap with other tumors harboring EWSR1-CREB1 and EWSR1-ATF1 fusions.
DATA SOURCES: Review of published literature, including case series, case reports, and review articles, in online medical databases.
CONCLUSIONS: The occurrence of AFH at several unusual anatomic sites and its spectrum of morphologic patterns can result in significant diagnostic difficulty, and correct diagnosis is particularly important because of its small risk of metastasis and death. This highlights the importance of diagnostic recognition, ancillary molecular genetic confirmation, and close clinical follow-up of patients with AFH. Further insight into the genetic and epigenetic changes arising secondary to the characteristic gene fusions of AFH will be integral to understanding its tumorigenic mechanisms.

Zhang L, Zhou Y, Cheng C, et al.
Genomic analyses reveal mutational signatures and frequently altered genes in esophageal squamous cell carcinoma.
Am J Hum Genet. 2015; 96(4):597-611 [PubMed] Free Access to Full Article Related Publications
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and the fourth most lethal cancer in China. However, although genomic studies have identified some mutations associated with ESCC, we know little of the mutational processes responsible. To identify genome-wide mutational signatures, we performed either whole-genome sequencing (WGS) or whole-exome sequencing (WES) on 104 ESCC individuals and combined our data with those of 88 previously reported samples. An APOBEC-mediated mutational signature in 47% of 192 tumors suggests that APOBEC-catalyzed deamination provides a source of DNA damage in ESCC. Moreover, PIK3CA hotspot mutations (c.1624G>A [p.Glu542Lys] and c.1633G>A [p.Glu545Lys]) were enriched in APOBEC-signature tumors, and no smoking-associated signature was observed in ESCC. In the samples analyzed by WGS, we identified focal (<100 kb) amplifications of CBX4 and CBX8. In our combined cohort, we identified frequent inactivating mutations in AJUBA, ZNF750, and PTCH1 and the chromatin-remodeling genes CREBBP and BAP1, in addition to known mutations. Functional analyses suggest roles for several genes (CBX4, CBX8, AJUBA, and ZNF750) in ESCC. Notably, high activity of hedgehog signaling and the PI3K pathway in approximately 60% of 104 ESCC tumors indicates that therapies targeting these pathways might be particularly promising strategies for ESCC. Collectively, our data provide comprehensive insights into the mutational signatures of ESCC and identify markers for early diagnosis and potential therapeutic targets.

Kummalue T, Inoue T, Miura Y, et al.
Ribosomal protein L11- and retinol dehydrogenase 11-induced erythroid proliferation without erythropoietin in UT-7/Epo erythroleukemic cells.
Exp Hematol. 2015; 43(5):414-423.e1 [PubMed] Related Publications
Erythropoiesis is the process of proliferation, differentiation, and maturation of erythroid cells. Understanding these steps will help to elucidate the basis of specific diseases associated with abnormal production of red blood cells. In this study, we continued our efforts to identify genes involved in erythroid proliferation. Lentivirally transduced UT-7/Epo erythroleukemic cells expressing ribosomal protein L11 (RPL11) or retinol dehydrogenase 11 (RDH11) could proliferate in the absence of erythropoietin, and their cell-cycle profiles revealed G0/G1 prolongation and low percentages of apoptosis. RPL11-expressing cells proliferated more rapidly than the RDH11-expressing cells. The antiapoptotic proteins BCL-XL and BCL-2 were expressed in both cell lines. Unlike the parental UT-7/Epo cells, the expression of hemoglobins (Hbs) in the transduced cells had switched from adult to fetal type. Several signal transduction pathways, including STAT5, were highly activated in transduced cells; furthermore, expression of the downstream target genes of STAT5, such as CCND1, was upregulated in the transduced cells. Taken together, the data indicate that RPL11 and RDH11 accelerate erythroid cell proliferation by upregulating the STAT5 signaling pathway with phosphorylation of Lyn and cyclic AMP response element-binding protein (CREB).

Wang J, Thway K
Clear cell sarcoma-like tumor of the gastrointestinal tract: an evolving entity.
Arch Pathol Lab Med. 2015; 139(3):407-12 [PubMed] Related Publications
Clear cell sarcoma-like tumor of the gastrointestinal tract (CCSLGT) is a rare malignant neoplasm that occurs in the wall of the small bowel, stomach, or large bowel, predominantly in young adults. It is an aggressive neoplasm that frequently presents with metastatic disease and has a high mortality rate. Histologically, it is usually composed of medium-sized primitive ovoid or epithelioid cells with pale or clear cytoplasm that are arranged in sheets or in papillary or alveolar architectures. Clear cell sarcoma-like tumor of the gastrointestinal tract is positive for S100 protein, invariably negative for melanocyte-specific markers and is often also positive for neuroendocrine markers. The etiology of CCSLGT is unknown, but many studies have shown associations with EWSR1-CREB1 gene fusions and, less frequently, with EWSR1-ATF1 fusions. Here, we discuss the current status of CCSLGT, including histologic, immunophenotypic, and molecular findings.

Green MR, Kihira S, Liu CL, et al.
Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation.
Proc Natl Acad Sci U S A. 2015; 112(10):E1116-25 [PubMed] Article available free on PMC after 10/09/2015 Related Publications
Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation.

Shoshan E, Mobley AK, Braeuer RR, et al.
Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis.
Nat Cell Biol. 2015; 17(3):311-21 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Although recent studies have shown that adenosine-to-inosine (A-to-I) RNA editing occurs in microRNAs (miRNAs), its effects on tumour growth and metastasis are not well understood. We present evidence of CREB-mediated low expression of ADAR1 in metastatic melanoma cell lines and tumour specimens. Re-expression of ADAR1 resulted in the suppression of melanoma growth and metastasis in vivo. Consequently, we identified three miRNAs undergoing A-to-I editing in the weakly metastatic melanoma but not in strongly metastatic cell lines. One of these miRNAs, miR-455-5p, has two A-to-I RNA-editing sites. The biological function of edited miR-455-5p is different from that of the unedited form, as it recognizes a different set of genes. Indeed, wild-type miR-455-5p promotes melanoma metastasis through inhibition of the tumour suppressor gene CPEB1. Moreover, wild-type miR-455 enhances melanoma growth and metastasis in vivo, whereas the edited form inhibits these features. These results demonstrate a previously unrecognized role for RNA editing in melanoma progression.

Takachi T, Takahashi M, Takahashi-Yoshita M, et al.
Human T-cell leukemia virus type 1 Tax oncoprotein represses the expression of the BCL11B tumor suppressor in T-cells.
Cancer Sci. 2015; 106(4):461-5 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia (ATL), which is an aggressive form of T-cell malignancy. HTLV-1 oncoproteins, Tax and HBZ, play crucial roles in the immortalization of T-cells and/or leukemogenesis by dysregulating the cellular functions in the host. Recent studies show that HTLV-1-infected T-cells have reduced expression of the BCL11B tumor suppressor protein. In the present study, we explored whether Tax and/or HBZ play a role in downregulating BCL11B in HTLV-1-infected T-cells. Lentiviral transduction of Tax in a human T-cell line repressed the expression of BCL11B at both the protein and mRNA levels, whereas the transduction of HBZ had little effect on the expression. Tax mutants with a decreased activity for the NF-κB, CREB or PDZ protein pathways still showed a reduced expression of the BCL11B protein, thereby implicating a different function of Tax in BCL11B downregulation. In addition, the HTLV-2 Tax2 protein reduced the BCL11B protein expression in T-cells. Seven HTLV-1-infected T-cell lines, including three ATL-derived cell lines, showed reduced BCL11B mRNA and protein expression relative to an uninfected T-cell line, and the greatest reductions were in the cells expressing Tax. Collectively, these results indicate that Tax is responsible for suppressing BCL11B protein expression in HTLV-1-infected T-cells; Tax-mediated repression of BCL11B is another mechanism that Tax uses to promote oncogenesis of HTLV-1-infected T-cells.

Stachowiak MK, Birkaya B, Aletta JM, et al.
"Nuclear FGF receptor-1 and CREB binding protein: an integrative signaling module".
J Cell Physiol. 2015; 230(5):989-1002 [PubMed] Related Publications
In this review we summarize the current understanding of a novel integrative function of Fibroblast Growth Factor Receptor-1 (FGFR1) and its partner CREB Binding Protein (CBP) acting as a nuclear regulatory complex. Nuclear FGFR1 and CBP interact with and regulate numerous genes on various chromosomes. FGFR1 dynamic oscillatory interactions with chromatin and with specific genes, underwrites gene regulation mediated by diverse developmental signals. Integrative Nuclear FGFR1 Signaling (INFS) effects the differentiation of stem cells and neural progenitor cells via the gene-controlling Feed-Forward-And-Gate mechanism. Nuclear accumulation of FGFR1 occurs in numerous cell types and disruption of INFS may play an important role in developmental disorders such as schizophrenia, and in metastatic diseases such as cancer. Enhancement of INFS may be used to coordinate the gene regulation needed to activate cell differentiation for regenerative purposes or to provide interruption of cancer stem cell proliferation.

Girgert R, Emons G, Gründker C
Inhibition of GPR30 by estriol prevents growth stimulation of triple-negative breast cancer cells by 17β-estradiol.
BMC Cancer. 2014; 14:935 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
BACKGROUND: Due to the lack of ERα, triple negative breast cancers (TNBCs) are not susceptible to endocrine therapy using antiestrogens. However, the majority of TNBCs express the membrane bound estrogen receptor GPR30. We have recently shown that knock-down of GPR30 expression prevented growth stimulation of TNBC cell lines by 17β-estradiol. Now we analyzed whether specific inhibition of GPR30 represents a new option for therapy of TNBC.
METHODS: Growth of TNBC cells was assessed using Alamar-blue colorimetric assay. Activation of c-Src and EGF-receptor was assessed using Western blots. Expression of c-fos, cyclin D1 and aromatase was quantified by RT-PCR. Gα-specific signaling of GPR30 was analyzed by electrophoretic mobility shift assay.
RESULTS: HCC1806 cells showed the highest GPR30 expression, in HCC70 cells it was clearly lower, in MDA-MB-231 cells it was lowest. 10-8 M 17β-estradiol significantly increased proliferation of HCC1806 cells to 134 ± 12% of control (p < 0.01). Proliferation of HCC70 cells was slightly increased to 116 ± 8% of control. Estriol significantly reduced cell number of HCC1806 cells to 16 ± 12% (p < 0.01). Cell number of HCC70 cells and of MDA-MB-231 cells was reduced to 68 ± 25% and to 61 ± 10%, respectively.Activity of Src kinase increased to 150 ± 10% (p < 0.05) by 10-8 M 17β-estradiol treatment in HCC1806 and to 220 ± 20% in HCC70 cells (p < 0.01). Estriol treatment completely inhibited 17β-estradiol-induced p-src activation. Transactivation of EGF-receptor increased by estradiol treatment to 350% in HCC1806 and to 280% in HCC70 cells. Estriol completely suppressed EGF-receptor transactivation. c-fos expression increased to 260% and to 190%, respectively. Estriol reduced this induction to 160% (HCC1806) and below control in HCC70 cells. Cyclin D1 was induced to 290% (HCC1806) and 170% (HCC70) and completely inhibited by estriol. 17β-estradiol increased CREB-phosphorylation to 400%. Binding of phospho-CREB to a CRE of cyclin D1 was enhanced to 320%.
CONCLUSION: Specific pharmacological inhibition of GPR30 might become a promising targeted therapy for TNBC in future.

Naderi A
Prolactin-induced protein in breast cancer.
Adv Exp Med Biol. 2015; 846:189-200 [PubMed] Related Publications
Prolactin-induced protein (PIP) is a 17-kDa single polypeptide chain that is secreted by a number of normal apocrine cells, such as milk, saliva, and seminal fluid. PIP is widely expressed in breast cancer and is commonly used as a diagnostic biomarker for the histopathological diagnosis of this disease. Expression of PIP in breast cancer is regulated by androgen and prolactin through a number of transcription factors and signaling cross-talks, including STAT5, Runx2, and CREB1. Notably, PIP is induced by a positive feedback loop between androgen receptor (AR) and extracellular signal-regulated kinase (ERK). The available data indicate that PIP has an aspartyl protease activity that can degrade fibronectin. Importantly, PIP is necessary for outside-in activation of integrin-β1 signaling pathway and regulation of key downstream signaling targets of this pathway such as interaction of integrin-β1 with integrin-linked kinase 1 (ILK1) and ErbB2. Furthermore, the importance of PIP in cell proliferation has been demonstrated by the fact that purified PIP promotes growth of breast cancer cells and PIP expression is necessary for the proliferation of T-47D and MDA-MB-453 cell lines. In addition to cell proliferation, PIP mediates invasion of breast cancer cells in a process that partially depends on the degradation of fibronectin by this protein. Therefore, PIP is a breast cancer-related protein that is expressed in a majority of breast tumors and has a significant function in the biology of this disease.

Cao C, Gao R, Zhang M, et al.
Role of LKB1-CRTC1 on glycosylated COX-2 and response to COX-2 inhibition in lung cancer.
J Natl Cancer Inst. 2015; 107(1):358 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
BACKGROUND: Cyclooxygenase-2 (COX-2) directs the synthesis of prostaglandins including PGE-2 linking inflammation with mitogenic signaling. COX-2 is also an anticancer target, however, treatment strategies have been limited by unreliable expression assays and by inconsistent tumor responses to COX-2 inhibition.
METHODS: We analyzed the TCGA and Director's Challenge lung cancer datasets (n = 188) and also generated an LKB1-null lung cancer gene signature (n = 53) to search the Broad Institute/Connectivity-MAP (C-MAP) dataset. We performed ChIP analyses, real-time polymerase chain reaction, immunoblotting, and drug testing of tumor cell lines (n = 8) and primary lung adenocarcinoma surgical resections (n = 13).
RESULTS: We show that COX-2 is a target of the cAMP/CREB coactivator CRTC1 signaling pathway. In addition, we detected a correlation between LKB1 status, CRTC1 activation, and presence of glycosylated, but not inactive hypoglycosylated COX-2 in primary lung adenocarcinoma. A search of the C-MAP drug database discovered that all high-ranking drugs positively associated with the LKB1-null signature are known CRTC1 activators, including forskolin and six different PGE-2 analogues. Somatic LKB1 mutations are present in 20.0% of lung adenocarcinomas, and we observed growth inhibition with COX-2 inhibitors in LKB1-null lung cancer cells with activated CRTC1 as compared with LKB1-wildtype cells (NS-398, P = .002 and Niflumic acid, P = .006; two-tailed t test).
CONCLUSION: CRTC1 activation is a key event that drives the LKB1-null mRNA signature in lung cancer. We also identified a positive feedback LKB1/CRTC1 signaling loop for COX-2/PGE2 regulation. These data suggest a role for LKB1 status and glycosylated COX-2 as specific biomarkers that provide a framework for selecting patients for COX-2 inhibition studies.

Xing C, Ci X, Sun X, et al.
Klf5 deletion promotes Pten deletion-initiated luminal-type mouse prostate tumors through multiple oncogenic signaling pathways.
Neoplasia. 2014; 16(11):883-99 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
Krüppel-like factor 5 (KLF5) regulates multiple biologic processes. Its function in tumorigenesis appears contradictory though, showing both tumor suppressor and tumor promoting activities. In this study, we examined whether and how Klf5 functions in prostatic tumorigenesis using mice with prostate-specific deletion of Klf5 and phosphatase and tensin homolog (Pten), both of which are frequently inactivated in human prostate cancer. Histologic analysis demonstrated that when one Pten allele was deleted, which causes mouse prostatic intraepithelial neoplasia (mPIN), Klf5 deletion accelerated the emergence and progression of mPIN. When both Pten alleles were deleted, which causes prostate cancer, Klf5 deletion promoted tumor growth, increased cell proliferation, and caused more severe morphologic and molecular alterations. Homozygous deletion of Klf5 was more effective than hemizygous deletion. Unexpectedly, while Pten deletion alone expanded basal cell population in a tumor as reported, Klf5 deletion in the Pten-null background clearly reduced basal cell population while expanding luminal cell population. Global gene expression profiling, pathway analysis, and experimental validation indicate that multiple mechanisms could mediate the tumor-promoting effect of Klf5 deletion, including the up-regulation of epidermal growth factor and its downstream signaling molecules AKT and ERK and the inactivation of the p15 cell cycle inhibitor. KLF5 also appears to cooperate with several transcription factors, including CREB1, Sp1, Myc, ER and AR, to regulate gene expression. These findings validate the tumor suppressor function of KLF5. They also yield a mouse model that shares two common genetic alterations with human prostate cancer-mutation/deletion of Pten and deletion of Klf5.

Felizola SJ, Nakamura Y, Ozawa Y, et al.
Activating transcription factor 3 (ATF3) in the human adrenal cortex: its possible involvement in aldosterone biosynthesis.
Tohoku J Exp Med. 2014; 234(4):249-54 [PubMed] Related Publications
The activating transcription factor 3 (ATF3) is a member of the cAMP-responsive element-binding (CREB) protein family of transcription factors. ATF3 is expressed in H295R human adrenocortical carcinoma cells and considered a rapid-responder gene to angiotensin-II stimulation. However, the functions of ATF3 in human adrenocortical tissues have remained unknown. In this study, we analyzed the localization and possible regulatory mechanisms of ATF3 in human adrenocortical cells and tissues. The expression levels of ATF3 mRNA were analyzed in 66 aldosterone-producing adenomas (APA) and 14 cortisol-producing adenomas (CPA) using real-time RT-PCR. To localize the ATF3 protein, we performed immunohistochemical analysis in 20 non-pathological adrenal glands, 9 adrenal glands with idiopathic hyperaldosteronism (IHA), 20 APA, and 5 CPA using a mouse monoclonal antibody against human ATF3. We showed that ATF3 mRNA levels were higher in APA compared to CPA (P = 0.0053). ATF3 was immunolocalized to the zona glomerulosa of non-pathological adrenal glands and adrenal glands with IHA, and diffusely detected in the tumor cells of APA and CPA. Subsequently, H295R cells were treated for 6 h with each inhibitor of Src kinase (SRC), PKC, JAK2, and calcium-dependent calmodulin kinase-II (CaMKII) in the presence or absence of angiotensin-II. The expression levels of ATF3 mRNA were increased by angiotensin-II (about 3.5-fold induction), but the magnitude of the induction was significantly decreased in the presence of an inhibitor for SRC (PP2) or CaMKII (KN93). These results suggest that ATF3 is a downstream target of SRC and CaMKII signaling, and may be involved in adrenocortical aldosterone synthesis.

Zhu YX, Yin H, Bruins LA, et al.
RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2.
Blood. 2015; 125(3):483-91 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
To identify molecular targets that modify sensitivity to lenalidomide, we measured proliferation in multiple myeloma (MM) cells transfected with 27 968 small interfering RNAs in the presence of increasing concentrations of drug and identified 63 genes that enhance activity of lenalidomide upon silencing. Ribosomal protein S6 kinase (RPS6KA3 or RSK2) was the most potent sensitizer. Other notable gene targets included 5 RAB family members, 3 potassium channel proteins, and 2 peroxisome family members. Single genes of interest included I-κ-B kinase-α (CHUK), and a phosphorylation dependent transcription factor (CREB1), which associate with RSK2 to regulate several signaling pathways. RSK2 knockdown induced cytotoxicity across a panel of MM cell lines and consistently increased sensitivity to lenalidomide. Accordingly, 3 small molecular inhibitors of RSK2 demonstrated synergy with lenalidomide cytotoxicity in MM cells even in the presence of stromal contact. Both RSK2 knockdown and small molecule inhibition downregulate interferon regulatory factor 4 and MYC, and provides an explanation for the synergy between lenalidomide and RSK2 inhibition. Interestingly, RSK2 inhibition also sensitized MM cells to bortezomib, melphalan, and dexamethasone, but did not downregulate Ikaros or influence lenalidomide-mediated downregulation of tumor necrosis factor-α or increase lenalidomide-induced IL-2 upregulation. In summary, inhibition of RSK2 may prove a broadly useful adjunct to MM therapy.

Guo W, Lu J, Dai M, et al.
Transcriptional coactivator CBP upregulates hTERT expression and tumor growth and predicts poor prognosis in human lung cancers.
Oncotarget. 2014; 5(19):9349-61 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
Upregulated expression and activation of human telomerase reverse transcriptase (hTERT) is a hallmarker of lung tumorigenesis. However, the mechanism underlying the aberrant hTERT activity in lung cancer cells remains poorly understood. In this study, we found the transcriptional co-activator CBP as a new hTERT promoter-binding protein that regulated hTERT expression and tumor growth in lung adenocarcinoma cells using a biotin-streptavidin-bead pulldown technique. Chromatin immunoprecipitation assay verified the immortalized cell and tumor cell-specific binding of CBP on hTERT promoter. Overexpression of exogenous CBP upregulated the expression of the hTERT promoter-driven luciferase and endogenous hTERT protein in lung cancer cells. Conversely, inhibition of CBP by CBP-specific siRNA or its chemical inhibitor repressed the expression of hTERT promoter-driven luciferase and endogenous hTERT protein as well as telomerase activity. Moreover, inhibition of CBP expression or activity also significantly reduced the proliferation of lung cancer cells in vitro and tumor growth in an xenograft mouse model in vivo. Immunohistochemical analysis of tissue microarrays of lung cancers revealed a positive correlation between CBP and hTERT. Importantly, the patients with high CBP and hTERT expression had a significantly shorter overall survival. Furthermore, CBP was found to interact with and acetylate transactivator Sp1 in lung cancer cells. Inhibition of CBP by CBP-specific siRNA or its chemical inhibitor significantly inhibited Sp1 acetylation and its binding to the hTERT promoter. Collectively, our results indicate that CBP contributes to the upregulation of hTERT expression and tumor growth, and overexpression of CBP predicts poor prognosis in human lung cancers.

Su B, Luo T, Zhu J, et al.
Interleukin-1β/Iinterleukin-1 receptor-associated kinase 1 inflammatory signaling contributes to persistent Gankyrin activation during hepatocarcinogenesis.
Hepatology. 2015; 61(2):585-97 [PubMed] Related Publications
UNLABELLED: Hepatocellular carcinoma (HCC) is a prototype of inflammation-associated cancer. Oncoprotein Gankyrin, which mostly increases in HCC, plays a critical role in HCC development and metastasis. However, the exact mechanism of Gankyrin up-regulation in HCC remains unclear. A Gankyrin luciferase reporter was developed to screen a potential regulator for Gankyrin from a list of proinflammatory cytokines, and interleukin (IL)-1β was found as one of its activators. In clinical premalignant and malignant liver disease samples, enhanced IL-1β/interleukin-1 receptor-associated kinase 1 (IRAK-1) signaling accompanied by increased Gankyrin was observed. Lower expression of Gankyrin and phospho-IRAK-1 are favorable prognostic markers for HCC. A similar correlation was observed in the diethylnitrosamine (DEN) model of rat hepatocarcinogenesis. The results from Gankyrin reporter activity, real-time polymerase chain reaction, or immunoblotting further confirmed the up-regulation of Gankyrin by IL-1β/IRAK-1 inflammatory signaling. Moreover, a series of Gankyrin's truncated reporters were constructed, and electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) were performed to analyze the properties of Gankyrin promoter. Mechanistically, the core promoter of Gankyrin contains the binding site of nuclear factor Y (NF-Y) family members, which can recruit histone acetyltransferase coactivator E1A-binding protein p300 (p300) or CREB-binding protein (CBP) to promote Gankyrin transcription. Conversely, knockdown of NF-Y, p300, or CBP inhibits Gankyrin expression. IL-1β stimulation causes sequential phosphorylation of IRAK-1, c-Jun N-terminal kinase (JNK), and p300 and enhances recruitment of the p300/CBP/NF-Y complex to Gankyrin promoter. Inhibition of phospho-JNK impairs IL-1β/IRAK-1 signaling-mediated up-regulation of Gankyrin.
CONCLUSION: The finding of IL-1β/IRAK-1 signaling promoting Gankyrin expression through JNK and NF-Y/p300/CBP complex provides a fresh view on inflammation-enhanced hepatocarcinogenesis.

Zuo Z, Che X, Wang Y, et al.
High mobility group Box-1 inhibits cancer cell motility and metastasis by suppressing activation of transcription factor CREB and nWASP expression.
Oncotarget. 2014; 5(17):7458-70 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
The ability to metastasize is a hallmark of malignant tumors, and metastasis is the principal cause of death of cancer patients. The High Mobility Group Box-1 (HMGB1) is a multifunction protein that serves as both a chromatin protein and an extracellular signaling molecule. Our current study demonstrated a novel mechanism of HMGB1 in the regulation of cancer cell actin polymerization, cell skeleton formation, cancer cell motility and metastasis. We found that knockdown of HMGB1 in human lung cancer A549 cells significantly increased cell β-actin polymerization, cell skeleton formation, cancer cell migration and invasion in vitro, as well as metastasis in vivo. And this increase could be inhibited by treatment of HMGB1 knockdown cells with recombinant human HMGB1. Further studies discovered that HMGB1 suppressed phosphorylation, nuclear translocation, and activation of CREB, by inhibiting nuclear translocation of PKA catalytic subunit. This reduces nWASP mRNA transcription and expression, further impairing cancer cell motility. Our findings on the novel mechanism underlying the HMGB1 anti-metastatic effect on cancer provides significant insight into the understanding of the nature of HMGB1 in cancer invasion and metastasis, further serving as key information for utilization of HMGB1 and its regulated downstream components as new targets for cancer therapy.

Yu W, Qiao Y, Tang X, et al.
Tumor suppressor long non-coding RNA, MT1DP is negatively regulated by YAP and Runx2 to inhibit FoxA1 in liver cancer cells.
Cell Signal. 2014; 26(12):2961-8 [PubMed] Related Publications
Recent studies are indicative for strong carcinogenetic roles of Runt related transcription factor 2 (Runx2) and Yes associated protein (YAP) in several cancer types. However, whether and how the interaction between Runx2 and YAP plays a role in liver tumorigenesis still remain illusive. Here, we identified a close relationship between Runx2 and YAP in liver cancer cells. Runx2 had a positive role on YAP expression and vice versa. We also found that Rux2 and YAP were capable of inhibiting long non-coding RNA (lncRNA), Metallothionein 1D, Pseudogene (MT1DP) expression through direct promoter binding. Overexpression of MT1DP resulted in reduced cell proliferation and colony formation in soft agar, but increased apoptosis in liver cancer cells, whereas knockdown of this lncRNA had the opposite effect, indicating that MT1DP acts as a tumor suppressor. Furthermore, MT1DP was revealed as a negative regulator of Alfa-fetoprotein (AFP), a classic liver cancer tumor marker, through inhibiting protein synthesis of Forkhead box A1 (FoxA1), an important transcription factor in liver development and cancer progression. Furthermore, we found that FoxA1 plays a positive role on YAP and Runx2 expression. Specially, opening the compacted chromatin by FoxA1 around CREB binding site within the YAP promoter facilitates CREB-mediated YAP transcription. Finally, MT1DP-inhibited in vivo liver cancer cell growth could be rescued by a combination of overexpression of FoxA1, Runx2 and YAP. Taken together, the close relationship between Rnux2 and YAP plays a pro-carcinogenetic role in liver cancer cells through inhibiting tumor suppressor lncRNA, MT1DP in a FoxA1 dependent manner.

Banerjee J, Al-Wadei HA, Al-Wadei MH, et al.
Differential modulation of nicotine-induced gemcitabine resistance by GABA receptor agonists in pancreatic cancer cell xenografts and in vitro.
BMC Cancer. 2014; 14:725 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
BACKGROUND: Pancreatic cancer is frequently resistant to cancer therapeutics. Smoking and alcoholism are risk factors and pancreatic cancer patients often undergo nicotine replacement therapy (NRT) and treatment for alcohol dependence. Based on our report that low dose nicotine within the range of NRT causes gemcitabine resistance in pancreatic cancer, our current study has tested the hypothesis that GABA or the selective GABA-B-R agonist baclofen used to treat alcohol dependence reverse nicotine-induced gemcitabine resistance in pancreatic cancer.
METHODS: Using mouse xenografts from the gemcitabine--sensitive pancreatic cancer cell line BXPC-3, we tested the effects of GABA and baclofen on nicotine-induced gemcitabine resistance. The levels of cAMP, p-SRC, p-ERK, p-AKT, p-CREB and cleaved caspase-3 in xenograft tissues were determined by ELISA assays. Expression of the two GABA-B receptors, metalloproteinase-2 and 9 and EGR-1 in xenograft tissues was monitored by Western blotting. Mechanistic studies were conducted in vitro, using cell lines BXPC-3 and PANC-1 and included analyses of cAMP production by ELISA assay and Western blots to determine protein expression of GABA-B receptors, metalloproteinase-2 and 9 and EGR-1.
RESULTS: Our data show that GABA was as effective as gemcitabine and significantly reversed gemcitabine resistance induced by low dose nicotine in xenografts whereas baclofen did not. These effects of GABA were accompanied by decreases in cAMP, p-CREB, p-AKT, p-Src, p-ERK metalloproteinases-9 and -2 and EGR-1 and increases in cleaved caspase-3 in xenografts whereas baclofen had the opposite effects. In vitro exposure of cells to single doses or seven days of nicotine induced the protein expression of MMP-2, MMP-9 and EGR-1 and these responses were blocked by GABA. Baclofen downregulated the protein expression of GABA-B-Rs in xenograft tissues and in cells exposed to baclofen for seven days in vitro. This response was accompanied by inversed baclofen effects from inhibition of cAMP formation after single dose exposures to stimulation of cAMP formation in cells pretreated for seven days.
CONCLUSIONS: These findings suggest GABA as a promising single agent for the therapy of pancreatic cancer and to overcome nicotine-induced gemcitabine resistance whereas treatment with baclofen may increase gemcitabine resistance.

Li Y, He Y, Qiu Z, et al.
CRTC2 and PROM1 expression in non-small cell lung cancer: analysis by Western blot and immunohistochemistry.
Tumour Biol. 2014; 35(12):11719-26 [PubMed] Related Publications
Accumulating evidence supports that genetic factors are another risk factors for lung cancer. Previously, we used whole exome sequencing with sanger sequencing to search for genetic-related mutations in one of four individuals from a pedigree with lung cancer history. Then, we used PCR-RFLP and direct-sequence in the sample size of 318 individuals with lung cancer (cases) and 272 controls. Recently, we detected two new genes including CRTC2 (CREB regulated transcription coactivator 2) and PROM1(human prominin-1,CD133). We investigated the CRTC2 mutation and PROM1 mutation of surgically resected NSCLC tissues (n=200). The presence or absence of CRTC2 and PROM1 mutation was analyzed by direct sequencing. The expression of CRTC2 and PROM1 was studied by western blot and immunohistochemical analysis of the lung cancer tissues which had the mutation of the two genes(cases), the samples without mutations(controls) and the normal lung tissue(controls). CRTC2 and PROM1 mutations in 5 NSCLC tissues and 3 NSCLC tissues out of the samples were identified. The positive results were closely correlated with clinicopathological features, such as male gender, adenocarcinoma, smoker status, and older age (≥55). We found that the CRTC2 and PROM1 expression were significantly higher in tissues of NSCLS with mutations than that without mutations and the normal lung tissue. The results imply that the high expression of CRTC2 and PROM1 may play an important role in the development and hereditary of NSCLC.

Jeon S, Kim Y, Chung IW, Kim YS
Clozapine induces chloride channel-4 expression through PKA activation and modulates CDK5 expression in SH-SY5Y and U87 cells.
Prog Neuropsychopharmacol Biol Psychiatry. 2015; 56:168-73 [PubMed] Related Publications
OBJECTIVES: Second-generation antipsychotic drugs, such as clozapine, were reported to enhance neurite outgrowth by nerve growth factor in PC12 cells. The authors previously showed that chloride channel 4 (CLC-4) is responsible for nerve growth factor-induced neurite outgrowth in neuronal cells. In this study, we examined whether clozapine induces CLC-4 in neuroblastoma and glioma cells.
METHODS: The effect of clozapine on CLC-4 expression was examined in neuroblastoma (SH-SY5Y) and glioma (U87) cells. To investigate the signaling pathway responsible for clozapine-induced CLC-4 expression, the phosphorylation of cAMP response element-binding protein (CREB), which binds CRE in the promoter of the human CLC-4 gene, was examined. To identify the target of clozapine induced CLC-4, CLC-4 siRNA was introduced to neuroblastoma and glioma cells for functional knockdown.
RESULTS: We observed that clozapine increased CLC-4 expression in both SH-SY5Y and U87 cells. Clozapine induced CREB phosphorylation, but in the presence of inhibitor of protein kinase A (an upstream kinase of CREB) clozapine-induced CLC-4 expression was suppressed. Finally, we found that CLC-4 knockdown suppressed clozapine-induced cyclin-dependent kinase 5 (CDK5) expression in SH-SY5Y and U-87 cells suggesting CDK5 as potential molecular target of clozapine induced CLC-4 expression.
CONCLUSIONS: The results of the present study suggest that clozapine's therapeutic effect may include the induction of CLC-4 which is dependent on CREB activation via PKA. We also found that functional knockdown of CLC-4 resulted in reduction of CDK5 expression, which may also be implicated in clozapine's therapeutic effect.

Turner-Ivey B, Guest ST, Irish JC, et al.
KAT6A, a chromatin modifier from the 8p11-p12 amplicon is a candidate oncogene in luminal breast cancer.
Neoplasia. 2014; 16(8):644-55 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
The chromosome 8p11-p12 amplicon is present in 12% to 15% of breast cancers, resulting in an increase in copy number and expression of several chromatin modifiers in these tumors, including KAT6A. Previous analyses in SUM-52 breast cancer cells showed amplification and overexpression of KAT6A, and subsequent RNAi screening identified KAT6A as a potential driving oncogene. KAT6A is a histone acetyltransferase previously identified as a fusion partner with CREB binding protein in acute myeloid leukemia. Knockdown of KAT6A in SUM-52 cells, a luminal breast cancer cell line harboring the amplicon, resulted in reduced growth rate compared to non-silencing controls and profound loss of clonogenic capacity both in mono-layer and in soft agar. The normal cell line MCF10A, however, did not exhibit slower growth with knockdown of KAT6A. SUM-52 cells with KAT6A knockdown formed fewer mammospheres in culture compared to controls, suggesting a possible role for KAT6A in self-renewal. Previous data from our laboratory identified FGFR2 as a driving oncogene in SUM-52 cells. The colony forming efficiency of SUM-52 KAT6A knockdown cells in the presence of FGFR inhibition was significantly reduced compared to cells with KAT6A knockdown only. These data suggest that KAT6A may be a novel oncogene in breast cancers bearing the 8p11-p12 amplicon. While there are other putative oncogenes in the amplicon, the identification of KAT6A as a driving oncogene suggests that chromatin-modifying enzymes are a key class of oncogenes in these cancers, and play an important role in the selection of this amplicon in luminal B breast cancers.

Jeon YK, Moon KC, Park SH, Chung DH
Primary pulmonary myxoid sarcomas with EWSR1-CREB1 translocation might originate from primitive peribronchial mesenchymal cells undergoing (myo)fibroblastic differentiation.
Virchows Arch. 2014; 465(4):453-61 [PubMed] Related Publications
Primary pulmonary myxoid sarcoma (PPMS) is a very rare lung tumor that has recently been shown to harbor an EWSR1-CREB1 translocation. However, the histogenesis and biological behavior of PPMS remains unclear. To provide insight into the histogenesis of PPMS, we studied surgical resection specimens of four patients, two females and two males with an age range of 26 to 65 years, all non-smokers with mild anemia. The tumors, three of which are endobronchial, measured between 4 and 13 cm. One patient developed metastasis to the contra-lateral lung 7 months after resection. Other patients remained alive without tumor for 1.5, 10, and 13 years. Fluorescence in situ hybridization (FISH) analysis with a gene break apart probe showed an EWSR1 translocation in all cases. The EWSR1-CREB1 fusion transcript was detected in all cases by reverse-transcription PCR. Immunohistochemical staining showed diffuse positive staining of the tumor cells only for vimentin. Tumor cells expressed no other myoid, epithelial, endothelial, melanocytic, myoepithelial, or neuroendocrine markers, except for smooth muscle actin and epithelial membrane antigen, which were only focally positive in individual cases. Ultrastructural analyses revealed the presence in the tumor cells of intermediate filaments with focal densities along the sub-cytoplasmic membrane as well as dense plaques. These results suggest that PPMS exhibits myofibroblastic differentiation. We conclude that PPMS is an intermediate grade malignant lung tumor harboring EWSR1 translocations, which may originate from mesenchymal cells that undergo fibroblastic or myofibroblastic differentiation.

Hui K, Yang Y, Shi K, et al.
The p38 MAPK-regulated PKD1/CREB/Bcl-2 pathway contributes to selenite-induced colorectal cancer cell apoptosis in vitro and in vivo.
Cancer Lett. 2014; 354(1):189-99 [PubMed] Related Publications
Supranutritional selenite has anti-cancer therapeutic effects in vivo; however, the detailed mechanisms underlying these effects are not clearly understood. Further studies would broaden our understanding of the anti-cancer effects of this compound and provide a theoretical basis for its clinical application. In this study, we primarily found that selenite exposure inhibited phosphorylation of cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB), leading to suppression of Bcl-2 in HCT116 and SW480 colorectal cancer (CRC) cells. Moreover, the selenite-induced inhibitory effect on PKD1 activation was involved in suppression of the CREB signalling pathway. Additionally, we discovered that selenite treatment can upregulate p38 MAPK phosphorylation, which results in inhibition of the PKD1/CREB/Bcl-2 survival pathway and triggers apoptosis. Finally, we established a colorectal cancer xenograft model and found that selenite treatment markedly inhibits tumour growth through the MAPK/PKD1/CREB/Bcl-2 pathway in vivo. Our results demonstrated that a supranutritional dose of selenite induced CRC cell apoptosis through inhibition of the PKD1/CREB/Bcl-2 axis both in vitro and in vivo.

Stockman DL, Ali SM, He J, et al.
Sclerosing epithelioid fibrosarcoma presenting as intraabdominal sarcomatosis with a novel EWSR1-CREB3L1 gene fusion.
Hum Pathol. 2014; 45(10):2173-8 [PubMed] Related Publications
We report a case of intraabdominal sclerosing epithelioid fibrosarcoma (SEF) with a t (11;22)(p11.2;q12.2) Ewing sarcoma breakpoint region 1-cAMP-responsive element-binding protein 3-like 1 translocation. A 43-year old man presented with massive ascites and shortness of breath. Imaging studies revealed a large mesenteric-based mass with extensive omental/peritoneal disease. After resection and cytoreductive surgery, the tumor recurred with metastasis to the lungs; the patient is still alive with disease. Histologically, there was a uniform population of epithelioid cells arranged in cords and nests, embedded in a dense collagenous matrix; no areas of low-grade fibromyxoid sarcoma were identified. All immunohistochemical markers were nonreactive. Fluorescence in situ hybridization studies showed rearrangement of Ewing sarcoma breakpoint region 1. Genomic profiling by clinical grade next-generation sequencing revealed a fusion gene between intron 11 of Ewing sarcoma breakpoint region 1 (22q12.2) and intron 5 of cAMP-responsive element-binding protein 3-like 1 (11p11.2). This is the first report of "pure" or true SEF presenting as intraabdominal sarcomatosis with confirmation of the recently described unique Ewing sarcoma breakpoint region 1-cAMP-responsive element-binding protein 3-like 1 gene fusion in SEF without areas of low-grade fibromyxoid sarcoma.

Vizcaíno C, Núñez LE, Morís F, Portugal J
Genome-wide modulation of gene transcription in ovarian carcinoma cells by a new mithramycin analogue.
PLoS One. 2014; 9(8):e104687 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
Ovarian cancer has a poor prognosis due to intrinsic or acquired resistance to some cytotoxic drugs, raising the interest in new DNA-binding agents such as mithramycin analogues as potential chemotherapeutic agents in gynecological cancer. Using a genome-wide approach, we have analyzed gene expression in A2780 human ovarian carcinoma cells treated with the novel mithramycin analogue DIG-MSK (demycarosyl-3D-β-D-digitoxosyl-mithramycin SK) that binds to C+G-rich DNA sequences. Nanomolar concentrations of DIG-MSK abrogated the expression of genes involved in a variety of cell processes including transcription regulation and tumor development, which resulted in cell death. Some of those genes have been associated with cell proliferation and poor prognosis in ovarian cancer. Sp1 transcription factor regulated most of the genes that were down-regulated by the drug, as well as the up-regulation of other genes mainly involved in response to cell stress. The effect of DIG-MSK in the control of gene expression by other transcription factors was also explored. Some of them, such as CREB, E2F and EGR1, also recognize C/G-rich regions in gene promoters, which encompass potential DIG-MSK binding sites. DIG-MSK affected several biological processes and molecular functions related to transcription and its cellular regulation in A2780 cells, including transcription factor activity. This new compound might be a promising drug for the treatment of ovarian cancer.

Xia S, Ma J, Bai X, et al.
Prostaglandin E2 promotes the cell growth and invasive ability of hepatocellular carcinoma cells by upregulating c-Myc expression via EP4 receptor and the PKA signaling pathway.
Oncol Rep. 2014; 32(4):1521-30 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) represents a major health problem worldwide. Prostaglandin E2 (PGE2), the predominant product of cyclooxygenase-2, has been implicated in hepatocarcinogenesis. However, the underlying molecular mechanisms remain to be further elucidated. c-myc, a cellular proto-oncogene, is activated or overexpressed in many types of human cancer, including HCC. The present study was designed to investigate the internal relationship and molecular mechanisms between PGE2 and c-Myc in HCC, and to define its role in HCC cell growth and invasion. Our results showed that PGE2 significantly upregulated c-Myc expression at both the mRNA and protein levels, and knockdown of c-Myc blocked PGE2-induced HCC cell growth and invasive ability in human HCC Huh-7 cells. The effect of PGE2 on c-Myc expression was mainly through the EP4 receptor, and EP4 receptor-mediated c-Myc protein upregulation largely depended on de novo biosynthesis of c-Myc mRNA and its protein. EP4 receptor signaling activated GS/AC and increased the intracellular cAMP level in Huh-7 cells. The adenylate cyclase (AC) activator forskolin mimicked the effects of the EP4 receptor agonist on c-Myc expression, while the AC inhibitor SQ22536 reduced EP4 receptor-mediated c-Myc upregulation. These data confirm the involvement of the GS/AC/cAMP pathway in EP4 receptor-mediated c-Myc upregulation. Moreover, the phosphorylation levels of CREB protein were markedly elevated by EP4 receptor signaling, and by using specific inhibitor and siRNA interference, we demonstrated that PKA/CREB was also involved in the EP4 receptor-mediated c-Myc upregulation. In summary, the present study revealed that PGE2 significantly upregulates c-Myc expression at both mRNA and protein levels through the EP4R/GS/AC/cAMP/PKA/CREB signaling pathway, thus promoting cell growth and invasion in HCC cells. Targeting of the PGE2/EP4R/c-Myc pathway may be a new therapeutic strategy to prevent and cure human HCC.

Lin CW, Chou YE, Chiou HL, et al.
Pterostilbene suppresses oral cancer cell invasion by inhibiting MMP-2 expression.
Expert Opin Ther Targets. 2014; 18(10):1109-20 [PubMed] Related Publications
OBJECTIVE: Polyphenol compounds, present in a wide variety of natural plants, exhibit antioxidant and free radical scavenging ability and induce apoptosis in various cancer cells. However, the effect of pterostilbene on oral cancer cell metastasis has not been clarified.
RESEARCH DESIGN AND METHODS: The present study aimed to examine the anti-metastatic properties of pterostilbene in human oral squamous cell carcinoma (SCC)-9 cells.
RESULTS: In this study, pterostilbene treatment significantly inhibited migration/invasion capacities of SCC-9 cells in vitro. The results of zymography and western blotting revealed that the activities and protein levels of the MMP-2 and urokinase-type plasminogen activator (u-PA) was inhibited by pterostilbene. Western blot analysis also showed that pterostilbene inhibits the phosphorylation of Akt, extracellular signal-regulated kinase 1/2 and p38. Determinations of the mRNA levels, real-time polymerase chain reaction and promoter assays were conducted to evaluate the inhibitory effects of pterostilbene on MMP-2 and u-PA expression in SCC-9 cells. Such inhibitory effects were associated with the upregulation of tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1 and the downregulation of the transcription factors of NF-κB, SP-1 and CREB signaling pathways.
CONCLUSIONS: Pterostilbene may have potential use as a chemopreventive agent against oral cancer metastasis.

Limm K, Wallner S, Milenkovic VM, et al.
The metabolite 5'-methylthioadenosine signals through the adenosine receptor A2B in melanoma.
Eur J Cancer. 2014; 50(15):2714-24 [PubMed] Related Publications
Several recent studies have shown evidence supporting the general knowledge that tumour cells exhibit changes in metabolism. It is becoming increasingly important to understand how these metabolic changes in tumour cells promote carcinogenesis and disease progression. We recently discovered a lack of methylthioadenosine phosphorylase (MTAP) expression in melanoma, which resulted in an accumulation of the metabolite 5'-methylthioadenosine (MTA) in melanoma cells and in the extracellular environment. MTA was shown to affect cell proliferation of surrounding stroma cells and cell invasiveness and the activation of the transcription factor activator protein-1 (AP-1) in melanoma cells. In this study, we addressed the regulation of cellular signalling by extracellular MTA accumulation. By focusing on putative receptors that could modulate MTA signalling, we identified the adenosine receptor ADORA2B as an important candidate. Knockdown experiments and the use of specific agonists and antagonists confirmed a link between MTA and AP-1 signalling through the ADORA2B receptor. Interestingly, stimulation of the cells with MTA did not result in activation of the classical cyclic adenosine monophosphate (cAMP) signalling cascades or in Ca(2+)-dependent signalling. We instead showed protein kinase C (PKC) signalling to be involved in MTA-mediated AP-1 activation. In summary, we identified ADORA2B to be the specific receptor and signalling pathway for the metabolite MTA. These findings may influence the use of MTA in a therapeutic manner.

Arensman MD, Telesca D, Lay AR, et al.
The CREB-binding protein inhibitor ICG-001 suppresses pancreatic cancer growth.
Mol Cancer Ther. 2014; 13(10):2303-14 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer due in part to a lack of highly robust cytotoxic or molecular-based therapies. Recent studies investigating ligand-mediated Wnt/β-catenin signaling have highlighted its importance in pancreatic cancer initiation and progression, as well as its potential as a therapeutic target in PDAC. The small-molecule ICG-001 binds cAMP-responsive element binding (CREB)-binding protein (CBP) to disrupt its interaction with β-catenin and inhibit CBP function as a coactivator of Wnt/β-catenin-mediated transcription. Given its ability to inhibit Wnt/β-catenin-mediated transcription in vitro and in vivo, as well as its efficacy in preclinical models of colorectal cancer and other Wnt-driven diseases, we examined ICG-001 and its potential role as a therapeutic in PDAC. ICG-001 alone significantly inhibited anchorage-dependent and -independent growth of multiple PDAC lines, and augmented in vitro growth inhibition when used in combination with gemcitabine. ICG-001 had only variable modest effects on PDAC apoptosis and instead mediated PDAC growth inhibition primarily through robust induction of G₁ cell-cycle arrest. These effects, however, seemed decoupled from its inhibition of Wnt/β-catenin-mediated transcription. DNA microarrays performed on PDAC cells in the context of ICG-001 treatment revealed ICG-001 altered the expression of several genes with well-established roles in DNA replication and cell-cycle progression, including direct actions on SKP2 and CDKN1A. ICG-001 also significantly prolonged survival in an in vivo orthotopic xenograft model of PDAC, indicating ICG-001 or derived compounds that disrupt CBP activity are potentially useful small-molecule therapeutics for pancreatic cancer.

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