Research IndicatorsGraph generated 16 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 16 March, 2017 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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: MEF2C (cancer-related)
Wang L, Li J, Zhao H, et al.Identifying the crosstalk of dysfunctional pathways mediated by lncRNAs in breast cancer subtypes.
Mol Biosyst. 2016; 12(3):711-20 [PubMed
] Related Publications
Crosstalk among abnormal pathways widely occurs in human cancer and generally leads to insensitivity to cancer treatment. How long non-coding RNAs (lncRNAs) participate in the regulation of an abnormal pathway crosstalk in human cancer is largely unknown. Here, we proposed a strategy that integrates mRNA and lncRNA expression profiles for systematic identification of lncRNA-mediated crosstalk among risk pathways in different breast cancer subtypes. We identified 12 to 44 crosstalking pathway pairs mediated by 28 to 49 lncRNAs in four breast cancer subtypes. An LncRNA-mediated crosstalking pathway network in each breast cancer subtype was then constructed. We observed a number of breast cancer subtype-specific crosstalks of risk pathways. These subtype-specific lncRNA-mediated pathway crosstalks largely determined subtype-selective functions. Notably, we observed that lncRNAs mediated the crosstalk of pathways by cooperating with known important protein-coding genes, which play core roles in the deterioration of breast cancer. And we also identified key lncRNAs contributing to the crosstalk network in each subtype. As an example, the low expression of LIFR-AS1 was associated with poor survival in LumB subtype, and its cooperated genes IL1R and TGFBR located at the most upstream of the MAPK signaling pathway shared a common cascade path (p38 MAPKs-MEF2C) that can result in proliferation, differentiation and apoptosis. In summary, we offer an effective way to characterize complex crosstalks mediated by lncRNAs in breast cancer subtypes, which can be applied to other diseases and provide useful information for understanding the pathogenesis of human cancer.
Laszlo GS, Alonzo TA, Gudgeon CJ, et al.High expression of myocyte enhancer factor 2C (MEF2C) is associated with adverse-risk features and poor outcome in pediatric acute myeloid leukemia: a report from the Children's Oncology Group.
J Hematol Oncol. 2015; 8:115 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Recent studies have identified myocyte enhancer factor 2C (MEF2C) as cooperating oncogene in acute myeloid leukemia (AML) and suggested a contribution to the aggressive nature of at least some subtypes of AML, raising the possibility that MEF2C could serve as marker of poor-risk AML and, therefore, have prognostic significance.
METHODS: To test this hypothesis, we retrospectively quantified MEF2C expression in pretreatment bone marrow specimens in participants of the AAML0531 trial by reverse-transcriptase polymerase chain reaction and correlated expression levels with disease characteristics and clinical outcome.
RESULTS: In all 751 available patient specimens, MEF2C messenger RNA (mRNA) was detectable and varied >3000-fold relative to β-glucuronidase. Patients with the highest relative MEF2C expression (4th quartile) less likely achieved a complete remission after one course of chemotherapy than the other patients (67 vs. 78 %, P = 0.005). They also had an inferior overall survival (P = 0.014; at 5 years 55 ± 8 vs. 67 ± 4 %), inferior event-free survival (P < 0.001; at 5 years 38 ± 7 vs. 54 ± 4 %), and higher relapse risk than patients within the lower 3 quartiles of MEF2C expression (P < 0.001; at 5 years 53 ± 9 vs. 35 ± 5 %). These differences were accounted for by lower prevalence of cytogenetically/molecularly defined low-risk disease (16 vs. 46 %, P < 0.001) and higher prevalence of standard-risk disease (68 vs. 42 %, P < 0.001) in patients with high MEF2C expression, suggesting that MEF2C cooperates with additional pathogenic abnormalities.
CONCLUSIONS: High MEF2C expression identifies a subset of AML patients with adverse-risk disease features and poor outcome. With confirmation that high MEF2C mRNA expression leads to overexpression of MEF2C protein, these findings provide the rationale for therapeutic targeting of MEF2C transcriptional activation in AML.
In Hodgkin lymphoma (HL) we recently identified deregulated expression of homeobox genes MSX1 and OTX2 which are physiologically involved in development of the embryonal neural plate border region. Here, we examined in HL homeobox gene SIX1 an additional regulator of this embryonal region mediating differentiation of placodal precursors. SIX1 was aberrantly activated in 12 % of HL patient samples in silico, indicating a pathological role in a subset of this B-cell malignancy. In addition, SIX1 expression was detected in HL cell lines which were used as models to reveal upstream factors and target genes of this basic developmental regulator. We detected increased copy numbers of the SIX1 locus at chromosome 14q23 correlating with enhanced expression while chromosomal translocations were absent. Moreover, comparative expression profiling data and pertinent gene modulation experiments indicated that the WNT-signalling pathway and transcription factor MEF2C regulate SIX1 expression. Genes encoding the transcription factors GATA2, GATA3, MSX1 and SPIB - all basic lymphoid regulators - were identified as targets of SIX1 in HL. In addition, cofactors EYA1 and TLE4, respectively, contrastingly mediated activation and suppression of SIX1 target gene expression. Thus, the protein domain interfaces may represent therapeutic targets in SIX1-positive HL subsets. Collectively, our data reveal a gene regulatory network with SIX1 centrally deregulating lymphoid differentiation and support concordance of lymphopoiesis/lymphomagenesis and developmental processes in the neural plate border region.
Cystatin D is an inhibitor of lysosomal and secreted cysteine proteases. Strikingly, cystatin D has been found to inhibit proliferation, migration, and invasion of colon carcinoma cells indicating tumor suppressor activity that is unrelated to protease inhibition. Here, we demonstrate that a proportion of cystatin D locates within the cell nucleus at specific transcriptionally active chromatin sites. Consistently, transcriptomic analysis show that cystatin D alters gene expression, including that of genes encoding transcription factors such as RUNX1, RUNX2, and MEF2C in HCT116 cells. In concordance with transcriptomic data, quantitative proteomic analysis identified 292 proteins differentially expressed in cystatin D-expressing cells involved in cell adhesion, cytoskeleton, and RNA synthesis and processing. Furthermore, using cytokine arrays we found that cystatin D reduces the secretion of several protumor cytokines such as fibroblast growth factor-4, CX3CL1/fractalkine, neurotrophin 4 oncostatin-M, pulmonary and activation-regulated chemokine/CCL18, and transforming growth factor B3. These results support an unanticipated role of cystatin D in the cell nucleus, controlling the transcription of specific genes involved in crucial cellular functions, which may mediate its protective action in colon cancer.
Myocyte enhancer factor 2B (MEF2B) is a transcription factor with mutation hotspots at K4, Y69 and D83 in diffuse large B-cell lymphoma (DLBCL). To provide insight into the regulatory network of MEF2B, in this study, we analyse global gene expression and DNA-binding patterns. We find that candidate MEF2B direct target genes include RHOB, RHOD, CDH13, ITGA5 and CAV1, and that indirect target genes of MEF2B include MYC, TGFB1, CARD11, MEF2C, NDRG1 and FN1. MEF2B overexpression increases HEK293A cell migration and epithelial-mesenchymal transition, and decreases DLBCL cell chemotaxis. K4E, Y69H and D83V MEF2B mutations decrease the capacity of MEF2B to activate transcription and decrease its' effects on cell migration. The K4E and D83V mutations decrease MEF2B DNA binding. In conclusion, our map of the MEF2B regulome connects MEF2B to drivers of oncogenesis.
Kawashima-Goto S, Imamura T, Tomoyasu C, et al.BCL2 Inhibitor (ABT-737): A Restorer of Prednisolone Sensitivity in Early T-Cell Precursor-Acute Lymphoblastic Leukemia with High MEF2C Expression?
PLoS One. 2015; 10(7):e0132926 [PubMed
] Free Access to Full Article Related Publications
Early T-cell precursor-acute lymphoblastic leukemia (ETP-ALL) has been identified as a high-risk subtype of pediatric T-cell acute lymphoblastic leukemia (T-ALL). Conventional chemotherapy is not fully effective for this subtype of leukemia; therefore, potential therapeutic targets need to be explored. Analysis of the gene expression patterns of the transcription factors in pediatric T-ALL revealed that MEF2C and FLT3 were expressed at higher levels in ETP-ALL than typical T-ALL. Using human T-ALL and BaF3 cell lines with high expression levels of MEF2C, the present study tested whether the BCL2 inhibitor (ABT-737) restores the sensitivity to prednisolone (PSL), because MEF2C causes PSL resistance, possibly by augmenting the anti-apoptotic activity of BCL2. Treatment with PSL and ABT-737 caused a significant reduction in the IC50 of PSL in the MEF2C-expressing LOUCY cells, in addition to the MEF2C-transduced BaF3 cells, but not in the non-MEF2C-expressing Jurkat cells. The combination treatment significantly accelerated the killing of primary leukemic blast cells of ETP-ALL with high expression levels of MEF2C, which were co-cultured with murine stromal cells. These findings suggest that BCL2 inhibitors may be a therapeutic candidate in vivo for patients with ETP-ALL with high expression levels of MEF2C.
Vitali C, Bassani C, Chiodoni C, et al.SOCS2 Controls Proliferation and Stemness of Hematopoietic Cells under Stress Conditions and Its Deregulation Marks Unfavorable Acute Leukemias.
Cancer Res. 2015; 75(11):2387-99 [PubMed
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Hematopoietic stem cells (HSC) promptly adapt hematopoiesis to stress conditions, such as infection and cancer, replenishing bone marrow-derived circulating populations, while preserving the stem cell reservoir. SOCS2, a feedback inhibitor of JAK-STAT pathways, is expressed in most primitive HSC and is upregulated in response to STAT5-inducing cytokines. We demonstrate that Socs2 deficiency unleashes HSC proliferation in vitro, sustaining STAT5 phosphorylation in response to IL3, thrombopoietin, and GM-CSF. In vivo, SOCS2 deficiency leads to unrestricted myelopoietic response to 5-fluorouracil (5-FU) and, in turn, induces exhaustion of long-term HSC function along serial bone marrow transplantations. The emerging role of SOCS2 in HSC under stress conditions prompted the investigation of malignant hematopoiesis. High levels of SOCS2 characterize unfavorable subsets of acute myeloid and lymphoblastic leukemias, such as those with MLL and BCR/ABL abnormalities, and correlate with the enrichment of genes belonging to hematopoietic and leukemic stemness signatures. In this setting, SOCS2 and its correlated genes are part of regulatory networks fronted by IKZF1/Ikaros and MEF2C, two transcriptional regulators involved in normal and leukemic hematopoiesis that have never been linked to SOCS2. Accordingly, a comparison of murine wt and Socs2(-/-) HSC gene expression in response to 5-FU revealed a significant overlap with the molecular programs that correlate with SOCS2 expression in leukemias, particularly with the oncogenic pathways and with the IKZF1/Ikaros and MEF2C-predicted targets. Lentiviral gene transduction of murine hematopoietic precursors with Mef2c, but not with Ikzf1, induces Socs2 upregulation, unveiling a direct control exerted by Mef2c over Socs2 expression.
Zheng R, Wang X, Studzinski GP1,25-Dihydroxyvitamin D3 induces monocytic differentiation of human myeloid leukemia cells by regulating C/EBPβ expression through MEF2C.
J Steroid Biochem Mol Biol. 2015; 148:132-7 [PubMed
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Myogenic enhancer factor2 (Mef2) consists of a family of transcription factors involved in morphogenesis of skeletal, cardiac and smooth muscle cells. Among the four isoforms (Mef2A, 2B, 2C, and 2D), Mef2C was also found to play important roles in hematopoiesis. At myeloid progenitor level, Mef2C expression favors monocytic differentiation. Previous studies from our laboratory demonstrated that ERK5 was activated in 1,25-dihydroxyvitamin D3 (1,25D)-induced monocytic differentiation in AML cells and ERK5 activation was accompanied by increased Mef2C phosphorylation. We therefore examined the role of Mef2C in 1,25D-induced monocytic differentiation in AML cell lines (HL60, U937 and THP1) and found that knockdown of Mef2C with small interfering RNA (siRNA) significantly decreases the expression of the monocytic marker, CD14, without affecting the expression of the general myeloid marker, CD11b. CCAAT/enhancer-binding protein (C/EBP) β, which can bind to CD14 promoter and increase its transcription, has been shown to be the downstream effector of 1,25D-induced monocytic differentiation in AML cells. When Mef2C was knocked down, expression of C/EBPβ was reduced at both mRNA and protein levels. The protein expression levels of cell cycle regulators, p27(Kip1) and cyclin D1, were not affected by Mef2C knockdown, nor the monopoiesis related transcription factor, ATF2 (activating transcription factor 2). Thus, we conclude that 1,25D-induced monocytic differentiation, and CD14 expression in particular, are mediated through activation of ERK5-Mef2C-C/EBPβ signaling pathway, and that Mef2C does not seem to modulate cell cycle progression.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Many cellular disruptions contribute to the progression of this pediatric cancer, including aberrant alternative splicing. The MEF2 family of transcription factors regulates many developmental programs, including myogenesis. MEF2 gene transcripts are subject to alternate splicing to generate protein isoforms with divergent functions. We found that MEF2Cα1 was the ubiquitously expressed isoform that exhibited no myogenic activity and that MEF2Cα2, the muscle-specific MEF2C isoform, was required for efficient differentiation. We showed that exon α in MEF2C was aberrantly alternatively spliced in RMS cells, with the ratio of α2/α1 highly down-regulated in RMS cells compared with normal myoblasts. Compared with MEF2Cα2, MEF2Cα1 interacted more strongly with and recruited HDAC5 to myogenic gene promoters to repress muscle-specific genes. Overexpression of the MEF2Cα2 isoform in RMS cells increased myogenic activity and promoted differentiation in RMS cells. We also identified a serine protein kinase, SRPK3, that was down-regulated in RMS cells and found that expression of SRPK3 promoted the splicing of the MEF2Cα2 isoform and induced differentiation. Restoration of either MEF2Cα2 or SPRK3 inhibited both proliferation and anchorage-independent growth of RMS cells. Together, our findings indicate that the alternative splicing of MEF2C plays an important role in normal myogenesis and RMS development. An improved understanding of alternative splicing events in RMS cells will potentially reveal novel therapeutic targets for RMS treatment.
Zhang JJ, Zhu Y, Xie KL, et al.Yin Yang-1 suppresses invasion and metastasis of pancreatic ductal adenocarcinoma by downregulating MMP10 in a MUC4/ErbB2/p38/MEF2C-dependent mechanism.
Mol Cancer. 2014; 13:130 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Increasing evidence indicates an important role of transcription factor Yin Yang-1 (YY1) in human tumorigenesis. However, its function in cancer remains controversial and the relevance of YY1 to pancreatic ductal adenocarcinoma (PDAC) remains to be clarified.
METHODS: In this study, we detected YY1 expression in clinical PDAC tissue samples and cell lines using quantitative RT-PCR, immunohistochemistry and western blotting. We also detected MUC4 and MMP10 mRNA levels in 108 PDAC samples using qRT-PCR and analyzed the correlations between YY1 and MUC4 or MMP10 expression. The role of YY1 in the proliferation, invasion and metastatic abilities of PDAC cells in vitro was studied by CCK-8 assay, cell migration and invasion assays. In vivo pancreatic tumor growth and metastasis was studied by a xenogenous subcutaneously implant model and a tail vein metastasis model. The potential mechanisms underlying YY1 mediated tumor progression in PDAC were explored by digital gene expression (DGE) sequencing, signal transduction pathways blockage experiments and luciferase assays. Statistical analysis was performed using the SPSS 15.0 software.
RESULTS: We found that the expression of YY1 in PDACs was higher compared with their adjacent non-tumorous tissues and normal pancreas tissues. However, PDAC patients with high level overexpression of YY1 had better outcome than those with low level overexpression. YY1 expression levels were statistically negatively correlated with MMP10 expression levels, but not correlated with MUC4 expression levels. YY1 overexpression suppressed, whereas YY1 knockdown enhanced, the proliferation, invasion and metastatic properties of BXPC-3 cells, both in vitro and in vivo. YY1 suppresses invasion and metastasis of pancreatic cancer cells by downregulating MMP10 in a MUC4/ErbB2/p38/MEF2C-dependent mechanism.
CONCLUSIONS: The present study suggested that YY1 plays a negative role, i.e. is a tumor suppressor, in PDAC, and may become a valuable diagnostic and prognostic marker of PDAC.
The pathogenesis of the cutaneous T-cell lymphoma (CTCL), mycosis fungoides (MF), is unclear. MicroRNA (miRNA) are small noncoding RNAs that target mRNA leading to reduced mRNA translation. Recently, specific miRNA were shown to be altered in CTCL. We detected significantly reduced expression of miR-223 in early-stage MF skin, and further decreased levels of miR-223 in advanced-stage disease. CTCL peripheral blood mononuclear cells and cell lines also had reduced miR-223 as compared with controls. Elevated expression of miR-223 in these cell lines reduced cell growth and clonogenic potential, whereas inhibition of miR-223 increased cell numbers. Investigations into putative miR-223 targets with oncogenic function, including E2F1 and MEF2C, and the predicted miR-223 target, TOX, revealed that all three were targeted by miR-223 in CTCL. E2F1, MEF2C, and TOX proteins were decreased with miR-223 overexpression, whereas miR-223 inhibition led to increased protein levels in CTCL. In addition, we showed that the 3'-UTR of TOX mRNA was a genuine target of miR-223. Therefore, reduced levels of miR-223 in MF/CTCL lead to increased expression of E2F1, MEF2C, and TOX, which likely contributes to the development and/or progression of CTCL. Thus, miR-223 and its targets may be useful for the development of new therapeutics for MF/CTCL.
Mitogen-activated protein kinases (MAPKs) are important transducers of external signals for cell growth, survival, and other cellular responses including cell differentiation. Several MAPK cascades are known with the MEK1/2-ERK1/2, JNK, and p38MAPKs receiving most attention, but the role of MEK5-ERK5 in intracellular signaling deserves more scrutiny, as this pathway transmits signals that can complement ERK/2 signaling. We hypothesized that the ERK5 pathway plays a role in the control of monocytic differentiation, which is disturbed in myeloid leukemia. We therefore examined the cellular phenotype and key molecular events which occur when human myeloid leukemia cells, acute (AML) or chronic (CML), are forced to differentiate by vitamin D derivatives (VDDs). This study was performed using established cell lines HL60 and U937, and primary cultures of blasts from 10 patients with ML. We found that ERK5 and its direct downstream target transcription factor MEF2C are upregulated by 1,25D in parallel with monocytic differentiation. Further, inhibition of ERK5 activity by specific pharmacological agents BIX02189 and XMD8-92 alters the phenotype of these cells by reducing the abundance of the VDD-induced surface monocytic marker CD14, and concomitantly increasing surface expression of the general myeloid marker CD11b. Similar results were obtained when the expression of ERK5 was reduced by siRNA or short hairpin (sh) RNA. ERK5 inhibition resulted in an expected decrease in MEF2C activation. We also found that in AML cells the transcription factor C/EBPβ is positively regulated, while C/EBPα is negatively regulated by ERK5. These findings provide new understanding of dysregulated differentiation in human myeloid leukemia.
He Y, Meng XM, Huang C, et al.Long noncoding RNAs: Novel insights into hepatocelluar carcinoma.
Cancer Lett. 2014; 344(1):20-7 [PubMed
] Related Publications
Recent advances in non-protein coding part of human genome analysis have discovered extensive transcription of large RNA transcripts that lack of coding protein function, termed long noncoding RNAs (lncRNAs). It is becoming evident that lncRNAs may be an important class of pervasive genes involved in carcinogenesis and metastasis. However, the biological and molecular mechanisms of lncRNAs in diverse diseases are not yet fully understood. Thus, it is anticipated that more efforts should be made to clarify the lncRNAs world. Moreover, accumulating studies have demonstrated that a class of lncRNAs are dysregulated in hepatocellular carcinoma(HCC) and closely related with tumorigenesis, metastasis, prognosis or diagnosis. In this review, we will briefly discuss the regulation and functional role of lncRNAs in HCC, therefore evaluating the potential of lncRNAs as prospective novel therapeutic targets in HCC.
Zuurbier L, Gutierrez A, Mullighan CG, et al.Immature MEF2C-dysregulated T-cell leukemia patients have an early T-cell precursor acute lymphoblastic leukemia gene signature and typically have non-rearranged T-cell receptors.
Haematologica. 2014; 99(1):94-102 [PubMed
] Free Access to Full Article Related Publications
Three distinct immature T-cell acute lymphoblastic leukemia entities have been described including cases that express an early T-cell precursor immunophenotype or expression profile, immature MEF2C-dysregulated T-cell acute lymphoblastic leukemia cluster cases based on gene expression analysis (immature cluster) and cases that retain non-rearranged TRG@ loci. Early T-cell precursor acute lymphoblastic leukemia cases exclusively overlap with immature cluster samples based on the expression of early T-cell precursor acute lymphoblastic leukemia signature genes, indicating that both are featuring a single disease entity. Patients lacking TRG@ rearrangements represent only 40% of immature cluster cases, but no further evidence was found to suggest that cases with absence of bi-allelic TRG@ deletions reflect a distinct and even more immature disease entity. Immature cluster/early T-cell precursor acute lymphoblastic leukemia cases are strongly enriched for genes expressed in hematopoietic stem cells as well as genes expressed in normal early thymocyte progenitor or double negative-2A T-cell subsets. Identification of early T-cell precursor acute lymphoblastic leukemia cases solely by defined immunophenotypic criteria strongly underestimates the number of cases that have a corresponding gene signature. However, early T-cell precursor acute lymphoblastic leukemia samples correlate best with a CD1 negative, CD4 and CD8 double negative immunophenotype with expression of CD34 and/or myeloid markers CD13 or CD33. Unlike various other studies, immature cluster/early T-cell precursor acute lymphoblastic leukemia patients treated on the COALL-97 protocol did not have an overall inferior outcome, and demonstrated equal sensitivity levels to most conventional therapeutic drugs compared to other pediatric T-cell acute lymphoblastic leukemia patients.
MacQuarrie KL, Yao Z, Fong AP, et al.Comparison of genome-wide binding of MyoD in normal human myogenic cells and rhabdomyosarcomas identifies regional and local suppression of promyogenic transcription factors.
Mol Cell Biol. 2013; 33(4):773-84 [PubMed
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Rhabdomyosarcoma is a pediatric tumor of skeletal muscle that expresses the myogenic basic helix-loop-helix protein MyoD but fails to undergo terminal differentiation. Prior work has determined that DNA binding by MyoD occurs in the tumor cells, but myogenic targets fail to activate. Using MyoD chromatin immunoprecipitation coupled to high-throughput sequencing and gene expression analysis in both primary human muscle cells and RD rhabdomyosarcoma cells, we demonstrate that MyoD binds in a similar genome-wide pattern in both tumor and normal cells but binds poorly at a subset of myogenic genes that fail to activate in the tumor cells. Binding differences are found both across genomic regions and locally at specific sites that are associated with binding motifs for RUNX1, MEF2C, JDP2, and NFIC. These factors are expressed at lower levels in RD cells than muscle cells and rescue myogenesis when expressed in RD cells. MEF2C is located in a genomic region that exhibits poor MyoD binding in RD cells, whereas JDP2 exhibits local DNA hypermethylation in its promoter in both RD cells and primary tumor samples. These results demonstrate that regional and local silencing of differentiation factors contributes to the differentiation defect in rhabdomyosarcomas.
Mastermind-like 1 (MAML1) is a transcriptional coregulator of activators in various signaling pathways, such as Notch, p53, myocyte enhancer factor 2C (MEF2C) and beta-catenin. In earlier studies, we demonstrated that MAML1 enhanced p300 acetyltransferase activity, which increased the acetylation of Notch by p300. In this study, we show that MAML1 strongly induced acetylation of the transcription factor early growth response-1 (EGR1) by p300, and increased EGR1 protein expression in embryonic kidney cells. EGR1 mRNA transcripts were also upregulated in the presence of MAML1. We show that MAML1 physically interacted with, and acted cooperatively with EGR1 to increase transcriptional activity of the EGR1 and p300 promoters, which both contain EGR1 binding sites. Bioinformatics assessment revealed a correlation between p300, EGR1 and MAML1 copy number and mRNA alterations in renal clear cell carcinoma and p300, EGR1 and MAML1 gene alterations were associated with increased overall survival. Our findings suggest MAML1 may be a component of the transcriptional networks which regulate EGR1 target genes during nephrogenesis and could also have implications for the development of renal cell carcinoma.
Metabolic transformations have been reported as involved in neoplasms survival. This suggests a role of metabolic pathways as potential cancer pharmacological targets. Modulating tumor's energy production pathways may become a substantial research area for cancer treatment. The significant role of metabolic deregulation as inducing transcriptional instabilities and consequently whole-system failure, is thus of foremost importance. By using a data integration approach that combines experimental evidence for high-throughput genome wide gene expression, a non-equilibrium thermodynamics analysis, nonlinear correlation networks as well as database mining, we were able to outline the role that transcription factors MEF2C and MNDA may have as main master regulators in primary breast cancer phenomenology, as well as the possible interrelationship between malignancy and metabolic dysfunction. The present findings are supported by the analysis of 1191 whole genome gene expression experiments, as well as probabilistic inference of gene regulatory networks, and non-equilibrium thermodynamics of such data. Other evidence sources include pathway enrichment and gene set enrichment analyses, as well as motif comparison with a comprehensive gene regulatory network (of homologue genes) in Arabidopsis thaliana. Our key finding is that the non-equilibrium free energies provide a realistic description of transcription factor activation that when supplemented with gene regulatory networks made us able to find deregulated pathways. These analyses also suggest a novel potential role of transcription factor energetics at the onset of primary tumor development. Results are important in the molecular systems biology of cancer field, since deregulation and coupling mechanisms between metabolic activity and transcriptional regulation can be better understood by taking into account the way that master regulators respond to physicochemical constraints imposed by different phenotypic conditions.
Yan L, Ping N, Zhu M, et al.Clinical, immunophenotypic, cytogenetic, and molecular genetic features in 117 adult patients with mixed-phenotype acute leukemia defined by WHO-2008 classification.
Haematologica. 2012; 97(11):1708-12 [PubMed
] Free Access to Full Article Related Publications
Among 4,780 consecutive adult acute lymphoblastic/myeloblastic leukemia patients, we identified 117 (2.4%) patients with mixed-phenotype acute leukemia fulfilling WHO 2008 criteria; these were classified as: Blymphoid+ myeloid (n=64), T-lymphoid+myeloid (n=38), B+T-lymphoid (n=14) and trilineage (n=1). Of 92 patients karyotyped, 59 were abnormal and were classified as: complex (22 of 92), t(9;22)(q34;q11) (14 of 92), monosomy 7 (7 of 92), polysomy 21 (7 of 92), t(v;11q23) (4 of 92), t(10;11)(p15;q21) (3 of 92), while STIL-TAL1 fusion was detected in one (T+My) patient. After investigating common acute leukemia-related mutations in 17 genes, 12 of 31 (39%) patients were found to have at least one mutation, classified with: IKZF1 deletion (4 of 31), and EZH2 (3 of 31), ASXL1 (3 of 31), ETV6 (2 of 31), NOTCH1 (1 of 31), and TET2 (1 of 31) mutations. Array-CGH revealed genomic deletions of CDKN2A (4 of 12), IKZF1 (3 of 12), MEF2C (2 of 12), BTG1 (2 of 12), together with BCOR, EBF1, K-RAS, LEF1, MBNL1, PBX3, and RUNX1 (one of 12 each). Our results indicate that mixed-phenotype acute leukemia is a complex entity with heterogeneous clinical, immunophenotypic, cytogenetic, and molecular genetic features.
BACKGROUND: Tumor-associated macrophages (TAMs) are alternatively activated cells induced by interleukin-4 (IL-4)-releasing CD4+ T cells. TAMs promote breast cancer invasion and metastasis; however, the mechanisms underlying these interactions between macrophages and tumor cells that lead to cancer metastasis remain elusive. Previous studies have found microRNAs (miRNAs) circulating in the peripheral blood and have identified microvesicles, or exosomes, as mediators of cell-cell communication. Therefore, one alternative mechanism for the promotion of breast cancer cell invasion by TAMs may be through macrophage-secreted exosomes, which would deliver invasion-potentiating miRNAs to breast cancer cells.
RESULTS: We utilized a co-culture system with IL-4-activated macrophages and breast cancer cells to verify that miRNAs are transported from macrophages to breast cancer cells. The shuttling of fluorescently-labeled exogenous miRNAs from IL-4-activated macrophages to co-cultivated breast cancer cells without direct cell-cell contact was observed. miR-223, a miRNA specific for IL-4-activated macrophages, was detected within the exosomes released by macrophages and was significantly elevated in the co-cultivated SKBR3 and MDA-MB-231 cells. The invasiveness of the co-cultivated breast cancer cells decreased when the IL-4-activated macrophages were treated with a miR-223 antisense oligonucleotide (ASO) that would inhibit miR-223 expression. Furthermore, results from a functional assay revealed that miR-223 promoted the invasion of breast cancer cells via the Mef2c-β-catenin pathway.
CONCLUSIONS: We conclude that macrophages regulate the invasiveness of breast cancer cells through exosome-mediated delivery of oncogenic miRNAs. Our data provide insight into the mechanisms underlying the metastasis-promoting interactions between macrophages and breast cancer cells.
Homminga I, Pieters R, Langerak AW, et al.Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia.
Cancer Cell. 2011; 19(4):484-97 [PubMed
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To identify oncogenic pathways in T cell acute lymphoblastic leukemia (T-ALL), we combined expression profiling of 117 pediatric patient samples and detailed molecular-cytogenetic analyses including the Chromosome Conformation Capture on Chip (4C) method. Two T-ALL subtypes were identified that lacked rearrangements of known oncogenes. One subtype associated with cortical arrest, expression of cell cycle genes, and ectopic NKX2-1 or NKX2-2 expression for which rearrangements were identified. The second subtype associated with immature T cell development and high expression of the MEF2C transcription factor as consequence of rearrangements of MEF2C, transcription factors that target MEF2C, or MEF2C-associated cofactors. We propose NKX2-1, NKX2-2, and MEF2C as T-ALL oncogenes that are activated by various rearrangements.
Nagel S, Venturini L, Przybylski GK, et al.Activation of Paired-homeobox gene PITX1 by del(5)(q31) in T-cell acute lymphoblastic leukemia.
Leuk Lymphoma. 2011; 52(7):1348-59 [PubMed
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In T-cell acute lymphoblasic leukemia (T-ALL), neoplastic chromosomal rearrangements are known to deregulate members of the homeobox gene families NKL and HOXA. Here, analysis of T-ALL cell lines and primary cells identified aberrant expression of a third homeobox gene group, the Paired (PRD) class. LOUCY cells revealed chromosomal deletion at 5q31, which targets the downstream regulatory region of the PRD homeobox gene PITX1, removing a STAT1 binding site. STAT1 mediates repressive interleukin 2 (IL2)-STAT1 signaling, implicating IL2 pathway avoidance as a possible activation mechanism. Among primary T-ALL samples, 2/22 (9%) aberrantly expressed PITX1, highlighting the importance of this gene. Forced expression of PITX1 in JURKAT cells and subsequent target gene analysis prompted deregulation of genes involved in T-cell development including HES1, JUN, NKX3-1, RUNX1, RUNX2, and TRIB2. Taken together, our data show leukemic activation of PITX1, a novice PRD-class homeobox gene in a subset of early-staged T-ALL, which may promote leukemogenesis by inhibiting T-cell development.
BACKGROUND: Cancer has remarkable complexity at the molecular level, with multiple genes, proteins, pathways and regulatory interconnections being affected. We introduce a systems biology approach to study cancer that formally integrates the available genetic, transcriptomic, epigenetic and molecular knowledge on cancer biology and, as a proof of concept, we apply it to colorectal cancer.
RESULTS: We first classified all the genes in the human genome into cancer-associated and non-cancer-associated genes based on extensive literature mining. We then selected a set of functional attributes proven to be highly relevant to cancer biology that includes protein kinases, secreted proteins, transcription factors, post-translational modifications of proteins, DNA methylation and tissue specificity. These cancer-associated genes were used to extract 'common cancer fingerprints' through these molecular attributes, and a Boolean logic was implemented in such a way that both the expression data and functional attributes could be rationally integrated, allowing for the generation of a guilt-by-association algorithm to identify novel cancer-associated genes. Finally, these candidate genes are interlaced with the known cancer-related genes in a network analysis aimed at identifying highly conserved gene interactions that impact cancer outcome. We demonstrate the effectiveness of this approach using colorectal cancer as a test case and identify several novel candidate genes that are classified according to their functional attributes. These genes include the following: 1) secreted proteins as potential biomarkers for the early detection of colorectal cancer (FXYD1, GUCA2B, REG3A); 2) kinases as potential drug candidates to prevent tumor growth (CDC42BPB, EPHB3, TRPM6); and 3) potential oncogenic transcription factors (CDK8, MEF2C, ZIC2).
CONCLUSION: We argue that this is a holistic approach that faithfully mimics cancer characteristics, efficiently predicts novel cancer-associated genes and has universal applicability to the study and advancement of cancer research.
Gupta N, Bhaskar AS, Lakshmana Rao PVTranscriptional regulation and activation of the mitogen-activated protein kinase pathway after Japanese encephalitis virus infection in neuroblastoma cells.
FEMS Immunol Med Microbiol. 2011; 62(1):110-21 [PubMed
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Japanese encephalitis virus (JEV), the most frequent and the single most important cause of encephalitis worldwide, has spread throughout most of Asia. For the development of appropriate and effective therapy, there is an immediate requirement to understand the role of host factors in JEV-induced neuropathogenesis. In the present study, we investigated the role of mitogen-activated protein kinases (MAPKs) in JEV infection of mouse neuroblastoma (N2A) cells. The MAPK pathway was studied at the transcriptional level to access the gene expression profile at different time points after JEV infection. The effector MAPK genes were also analyzed for protein expression and activation. Gene expression analysis showed a significant regulation of extracellular signal-regulated kinases (ERK)1, ERK2 and c-Jun N-terminal kinase (JNK)3 genes along with their downstream transcription factors such as Mef2c, c-Jun and Sfn. Experiments with the JNK inhibitor, SP600125, and the ERK inhibitor, PD98059, showed the involvement of JNK in JEV-induced caspase-3 activation and apoptosis, but ERK1/2 had no effect. Overall, our results show the transcriptional regulation of the MAPK pathway and the essential role of JNK in JEV-induced apoptosis in neuroblastoma cells. These findings provide a new insight into the role of the mitogen- and stress-activated kinases in JEV pathogenesis and opens up new avenues of therapeutics.
Nagel S, Venturini L, Meyer C, et al.Transcriptional deregulation of oncogenic myocyte enhancer factor 2C in T-cell acute lymphoblastic leukemia.
Leuk Lymphoma. 2011; 52(2):290-7 [PubMed
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Myocyte enhancer factor 2C (MEF2C) encodes a transcription factor which is ectopically expressed in T-cell acute lymphoblastic leukemia (T-ALL) cell lines, deregulated directly by ectopically expressed homeodomain protein NKX2-5 or by loss of promoter regions via del(5)(q14). Here, we analyzed the MEF2C 5'-region, thus identifying potential regulatory binding sites for GFI1B, basic helix-loop-helix proteins, STAT5, and HOXA9/HOXA10. Chromatin immunoprecipitation and overexpression analyses demonstrated direct activation by GFI1B and LYL1 and inhibition by STAT5. HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5. Lacking comma: Chromosomal deletion of the STAT5 binding site in LOUCY cells reduced protein levels of STAT5 in some MEF2C-positve T-ALL cell lines, and the presence of inhibitory IL7-JAK-STAT5 signaling highlighted the repressive impact of this factor in MEF2C regulation. Taken together, our results indicate that the expression of MEF2C in T-ALL cells is principally deregulated via activating leukemic transcription factors GFI1B or NKX2-5 and by escaping inhibitory developmental STAT5 signaling.
BACKGROUND: Most patients with ovarian cancer are diagnosed with advanced stage disease (i.e., stage III-IV), which is associated with a poor prognosis. Differentially expressed genes (DEGs) in stage III serous ovarian carcinoma compared to normal tissue were screened by a new differential display method, the annealing control primer (ACP) system. The potential targets for markers that could be used for diagnosis and prognosis, for stage III serous ovarian cancer, were found by cluster and survival analysis.
METHODS: The ACP-based reverse transcriptase polymerase chain reaction (RT PCR) technique was used to identify DEGs in patients with stage III serous ovarian carcinoma. The DEGs identified by the ACP system were confirmed by quantitative real-time PCR. Cluster analysis was performed on the basis of the expression profile produced by quantitative real-time PCR and survival analysis was carried out by the Kaplan-Meier method and Cox proportional hazards multivariate model; the results of gene expression were compared between chemo-resistant and chemo-sensitive groups.
RESULTS: A total of 114 DEGs were identified by the ACP-based RT PCR technique among patients with stage III serous ovarian carcinoma. The DEGs associated with an apoptosis inhibitory process tended to be up-regulated clones while the DEGs associated with immune response tended to be down-regulated clones. Cluster analysis of the gene expression profile obtained by quantitative real-time PCR revealed two contrasting groups of DEGs. That is, a group of genes including: SSBP1, IFI6 DDT, IFI27, C11orf92, NFKBIA, TNXB, NEAT1 and TFG were up-regulated while another group of genes consisting of: LAMB2, XRCC6, MEF2C, RBM5, FOXP1, NUDCP2, LGALS3, TMEM185A, and C1S were down-regulated in most patients. Survival analysis revealed that the up-regulated genes such as DDAH2, RNase K and TCEAL2 might be associated with a poor prognosis. Furthermore, the prognosis of patients with chemo-resistance was predicted to be very poor when genes such as RNase K, FOXP1, LAMB2 and MRVI1 were up-regulated.
CONCLUSION: The DEGs in patients with stage III serous ovarian cancer were successfully and reliably identified by the ACP-based RT PCR technique. The DEGs identified in this study might help predict the prognosis of patients with stage III serous ovarian cancer as well as suggest targets for the development of new treatment regimens.
Schwieger M, Schüler A, Forster M, et al.Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C.
Blood. 2009; 114(12):2476-88 [PubMed
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Acute myelogenous leukemia is driven by leukemic stem cells (LSCs) generated by mutations that confer (or maintain) self-renewal potential coupled to an aberrant differentiation program. Using retroviral mutagenesis, we identified genes that generate LSCs in collaboration with genetic disruption of the gene encoding interferon response factor 8 (Irf8), which induces a myeloproliferation in vivo. Among the targeted genes, we identified Mef2c, encoding a MCM1-agamous-deficiens-serum response factor transcription factor, and confirmed that overexpression induced a myelomonocytic leukemia in cooperation with Irf8 deficiency. Strikingly, several of the genes identified in our screen have been reported to be up-regulated in the mixed-lineage leukemia (MLL) subtype. High MEF2C expression levels were confirmed in acute myelogenous leukemia patient samples with MLL gene disruptions, prompting an investigation of the causal interplay. Using a conditional mouse strain, we demonstrated that Mef2c deficiency does not impair the establishment or maintenance of LSCs generated in vitro by MLL/ENL fusion proteins; however, its loss led to compromised homing and invasiveness of the tumor cells. Mef2c-dependent targets included several genes encoding matrix metalloproteinases and chemokine ligands and receptors, providing a mechanistic link to increased homing and motility. Thus, MEF2C up-regulation may be responsible for the aggressive nature of this leukemia subtype.
We previously reported hedgehog (Hh) signal activation in the mucus-secreting pit cell of the stomach and in diffuse-type gastric cancer (GC). Epithelial-mesenchymal transition (EMT) is known to be involved in tumour malignancy. However, little is known about whether and how both signallings cooperatively act in diffuse-type GC. By microarray and reverse transcription-PCR, we investigated the expression of those Hh and EMT signalling molecules in pit cells and in diffuse-type GCs. How both signallings act cooperatively in those cells was also investigated by the treatment of an Hh-signal inhibitor and siRNAs of Hh and EMT transcriptional key regulator genes on a mouse primary culture and on human GC cell lines. Pit cells and diffuse-type GCs co-expressed many Hh and EMT signalling genes. Mesenchymal-related genes (WNT5A, CDH2, PDGFRB, EDNRA, ROBO1, ROR2, and MEF2C) were found to be activated by an EMT regulator, SIP1/ZFHX1B/ZEB2, which was a target of a primary transcriptional regulator GLI1 in Hh signal. Furthermore, we identified two cancer-specific Hh targets, ELK1 and MSX2, which have an essential role in GC cell growth. These findings suggest that the gastric pit cell exhibits mesenchymal-like gene expression, and that diffuse-type GC maintains expression through the Hh-EMT pathway. Our proposed extensive Hh-EMT signal pathway has the potential to an understanding of diffuse-type GC and to the development of new drugs.
Leukemias that harbor translocations involving the mixed lineage leukemia gene (MLL) possess unique biologic characteristics and often have an unfavorable prognosis. Gene expression analyses demonstrate a distinct profile for MLL-rearranged leukemias with consistent high-level expression of select Homeobox genes, including HOXA9. Here, we investigated the effects of HOXA9 suppression in MLL-rearranged and MLL-germline leukemias using RNA interference. Gene expression profiling after HOXA9 suppression demonstrated co-down-regulation of a program highly expressed in human MLL-AML and murine MLL-leukemia stem cells, including HOXA10, MEIS1, PBX3, and MEF2C. We demonstrate that HOXA9 depletion in 17 human AML/ALL cell lines (7 MLL-rearranged, 10 MLL-germline) induces proliferation arrest and apoptosis specifically in MLL-rearranged cells (P = .007). Similarly, assessment of primary AMLs demonstrated that HOXA9 suppression induces apoptosis to a greater extent in MLL-rearranged samples (P = .01). Moreover, mice transplanted with HOXA9-depleted t(4;11) SEMK2 cells revealed a significantly lower leukemia burden, thus identifying a role for HOXA9 in leukemia survival in vivo. Our data indicate an important role for HOXA9 in human MLL-rearranged leukemias and suggest that targeting HOXA9 or downstream programs may be a novel therapeutic option.
Qiu Y, Michalak MTranscriptional control of the calreticulin gene in health and disease.
Int J Biochem Cell Biol. 2009; 41(3):531-8 [PubMed
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Calreticulin is a multifunctional Ca(2+) binding chaperone in the endoplasmic reticulum and expression of the protein is tightly regulated at the transcriptional level. There are two calreticulin genes, named calreticulin-1 and calreticulin-2 gene. The calreticulin-1 promoter contains a number of putative binding sites for transcription factors including tissue specific factors. Direct regulation of the calreticulin-1 promoter by several of these factors has been confirmed experimentally including Nkx2.5, MEF2C, GATA6, PPAR, COUP-TF1 and Evi-1 factors. Studies on calreticulin-deficient mice and transgenic animal models indicate that calreticulin is critical for cardiac development and that expression of the protein must be tightly regulated during cardiogenesis. Moreover, differential expression of calreticulin has been associated with several diseases, including neurodegenerative problems, cancers, autoimmune diseases and wound healing. Understanding the mechanisms responsible for the regulation of expression of calreticulin may contribute to the treatment of many diverse diseases.
McElhinny AS, Li JL, Wu LMastermind-like transcriptional co-activators: emerging roles in regulating cross talk among multiple signaling pathways.
Oncogene. 2008; 27(38):5138-47 [PubMed
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A family of Mastermind-like (MAML) genes encodes critical transcriptional co-activators for Notch signaling, an evolutionarily conserved pathway with numerous roles in both development and human diseases. Notch receptors are cleaved upon ligand engagement and the intracellular domain of Notch shuttles to the nucleus. MAMLs form a functional DNA-binding complex with the cleaved Notch receptor and the transcription factor CSL, thereby regulating transcriptional events that are specific to the Notch pathway. Here, we review recent studies that have utilized molecular, cellular and physiological model system strategies to reveal the pivotal roles of the MAML proteins in Notch signaling. Unexpectedly, however, emerging evidence implicate MAML proteins as exciting key transcriptional co-activators in other signal transduction pathways including: muscle differentiation and myopathies (MEF2C), tumor suppressor pathway (p53) and colon carcinoma survival (beta-catenin). Thus, the MAML family appears to function in transcriptional co-activation in a multitude of cellular processes. It is hypothesized that MAML proteins mediate cross-talk among the various signaling pathways and the diverse activities of the MAML proteins converge to impact normal biological processes and human diseases, including cancers.