Gene Summary

Gene:DACH1; dachshund family transcription factor 1
Aliases: DACH
Summary:This gene encodes a chromatin-associated protein that associates with other DNA-binding transcription factors to regulate gene expression and cell fate determination during development. The protein contains a Ski domain that is highly conserved from Drosophila to human. Expression of this gene is lost in some forms of metastatic cancer, and is correlated with poor prognosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:dachshund homolog 1
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
Show (17)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 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.

  • Leukaemia
  • Oncogene Fusion Proteins
  • Protein Binding
  • Gene Expression
  • Promoter Regions
  • Signal Transduction
  • Oligonucleotide Array Sequence Analysis
  • Protein Structure, Tertiary
  • Cancer Gene Expression Regulation
  • Triazoles
  • Drug Resistance
  • Neoplasm Invasiveness
  • Mutation
  • Western Blotting
  • Cell Line
  • Wnt Signaling Pathway
  • Transcription
  • Apoptosis
  • Gene Expression Profiling
  • HEK293 Cells
  • Homeodomain Proteins
  • Staging
  • Eye Proteins
  • DNA Methylation
  • Cell Movement
  • Epigenetics
  • Biomarkers, Tumor
  • Transforming Growth Factor beta
  • Adenocarcinoma
  • Y-Box-Binding Protein 1
  • Lung Cancer
  • Tamoxifen
  • Messenger RNA
  • Immunohistochemistry
  • Genome-Wide Association Study
  • Chromosome 13
  • Breast Cancer
  • Cell Proliferation
  • Young Adult
  • Repressor Proteins
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: DACH1 (cancer-related)

Zhang S, Liu X, Liu J, et al.
PGC-1 alpha interacts with microRNA-217 to functionally regulate breast cancer cell proliferation.
Biomed Pharmacother. 2017; 85:541-548 [PubMed] Related Publications
BACKGROUND: In this study, we explored the functional mechanism of PPARg co-activator 1-alpha (PGC-1α) in regulating miR-217-mediated breast cancer development in vitro.
METHODS: Dual-luciferase activity assay was applied to examine the binding of miR-217 on PGC-1α gene. Breast cancer cell lines, MCF-7 and MDA-MB-231 were infected by lentivirus to constitutively downregulate miR-217. Its regulation on PGC-1α expression was investigated by qRT-PCR and western blot. PGC-1α gene was subsequently downregulated by siRNA in miR-217-downregulated breast cancer cells to examine its effect on cancer proliferation and cell-cycle progression. In addition, another downstream target gene of miR-217, DACH1, was further downregulated in breast cancer cells to investigate the functional association of PGC-1α and DACH1 in miR-217-mediated breast cancer regulation.
RESULTS: PGC-1α gene was directly bound by human miR-217. Downregulation of miR-217 in MCF-7 and MDA-MB-231 cells increased PGC-1α production at both mRNA and protein levels. SiRNA-mediated PGC-1α downregulation reversed the inhibition of miR-217-downregulaiton on breast cancer proliferation and cell-cycle progression. Moreover, siRNA-mediated DACH1 downregulation further reversed miR-217-downregulaiton induced inhibition on cancer proliferation and cell-cycle progression in PGC-1α downregulated MCF-7 and MDA-MB-231 cells.
CONCLUSION: MiR-217 is the upstream regulator of PGC-1α in breast cancer regulation in vitro, possibly independent of DACH1 signaling pathway.

Bu XN, Qiu C, Wang C, Jiang Z
Inhibition of DACH1 activity by short hairpin RNA represses cell proliferation and tumor invasion in pancreatic cancer.
Oncol Rep. 2016; 36(2):745-54 [PubMed] Related Publications
Cancer of the pancreas is one of the most lethal diseases worldwide. Better understanding of the molecular mechanisms involved in tumorigenesis is of great consequence to elevate the survival rate. Human Dachshund homologue 1 (DACH1) plays a controversial role in human malignancy progression with its expression being altered in a variety of cancers. Nevertheless, its functional roles and molecular mechanisms in pancreatic cancer remain unknown. The expression of DACH1 in pancreatic cancer cell lines and the ductal epithelial cells were evaluated both at mRNA and protein levels. Three pairs of siRNA targeting the DACH1 gene were designed and synthesized, double-stranded short hairpin RNA (shRNA) were annealed and inserted into pGenesil-1 vector, which was confirmed by enzymatic digestion and sequencing analyses. The successfully constructed recombinant plasmids were transfected into Capan-1 cells and our data indicated that knockdown of DACH1 gene expression showed strong correlation with repressing tumorigenesis. The proliferation of Capan-1 cells was significantly repressed as evaluated by CCK-8 and colony formation assays. Flow cymetry revealed that cell apoptosis was promoted in interference plasmid group compared with control groups (P<0.05), whereas cell cycle had no significant differences among the groups (P>0.05). Transwell assay validated the abilities of migration and invasion as being significantly reduced in pshRNA-DACH1 group. Furthermore, our study suggested that DACH1 expression regulates the pancreatic cancer cell apoptosis through interacting with Bcl-2 signaling axis, whereas it controls cell migration and invasion via epithelial-mesenchymal transition (EMT) process.

Kim SH, Kaschula CH, Priedigkeit N, et al.
Forkhead Box Q1 Is a Novel Target of Breast Cancer Stem Cell Inhibition by Diallyl Trisulfide.
J Biol Chem. 2016; 291(26):13495-508 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
Diallyl trisulfide (DATS), a metabolic byproduct of garlic, is known to inhibit the growth of breast cancer cells in vitro and in vivo This study demonstrates that DATS targets breast cancer stem cells (bCSC). Exposure of MCF-7 and SUM159 human breast cancer cells to pharmacological concentrations of DATS (2.5 and 5 μm) resulted in dose-dependent inhibition of bCSC, as evidenced by a mammosphere assay and flow cytometric analysis of aldehyde dehydrogenase 1 (ALDH1) activity and the CD44(high)/CD24(low)/epithelial specific antigen-positive fraction. DATS-mediated inhibition of bCSC was associated with a decrease in the protein level of FoxQ1. Overexpression of FoxQ1 in MCF-7 and SUM159 cells increased ALDH1 activity and the CD49f(+)/CD24(-) fraction. Inhibition of ALDH1 activity and/or mammosphere formation upon DATS treatment was significantly attenuated by overexpression of FoxQ1. In agreement with these results, stable knockdown of FoxQ1 using small hairpin RNA augmented bCSC inhibition by DATS. Expression profiling for cancer stem cell-related genes suggested that FoxQ1 may negatively regulate the expression of Dachshund homolog 1 (DACH1), whose expression is lost in invasive breast cancer. Chromatin immunoprecipitation confirmed recruitment of FoxQ1 at the DACH1 promoter. Moreover, inducible expression of DACH1 augmented DATS-mediated inhibition of bCSC. Expression of FoxQ1 protein was significantly higher in triple-negative breast cancer cases compared with normal mammary tissues. Moreover, an inverse association was observed between FoxQ1 and DACH1 gene expression in breast cancer cell lines and tumors. DATS administration inhibited ALDH1 activity in vivo in SUM159 xenografts. These results indicate that FoxQ1 is a novel target of bCSC inhibition by DATS.

Ma K, Cao B, Guo M
The detective, prognostic, and predictive value of DNA methylation in human esophageal squamous cell carcinoma.
Clin Epigenetics. 2016; 8:43 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
Esophageal cancer is one of the most common malignancies in the world. Squamous cell carcinoma accounts for approximately 90 % of esophageal cancer cases. Genetic and epigenetic changes have been found to accumulate during the development of various cancers, including esophageal squamous carcinoma (ESCC). Tobacco smoking and alcohol consumption are two major risk factors for ESCC, and both tobacco and alcohol were found to induce methylation changes in ESCC. Growing evidence demonstrates that aberrant epigenetic changes play important roles in the multiple-step processes of carcinogenesis and tumor progression. DNA methylation may occur in the key components of cancer-related signaling pathways. Aberrant DNA methylation affects genes involved in cell cycle, DNA damage repair, Wnt, TGF-β, and NF-κB signaling pathways, including P16, MGMT, SFRP2, DACH1, and ZNF382. Certain genes methylated in precursor lesions of the esophagus demonstrate that DNA methylation may serve as esophageal cancer early detection marker, such as methylation of HIN1, TFPI-2, DACH1, and SOX17. CHFR methylation is a late stage event in ESCC and is a sensitive marker for taxanes in human ESCC. FHIT methylation is associated with poor prognosis in ESCC. Aberrant DNA methylation changes may serve as diagnostic, prognostic, and chemo-sensitive markers. Characterization of the DNA methylome in ESCC will help to better understand its mechanisms and develop improved therapies.

Zhu J, Wu C, Li H, et al.
DACH1 inhibits the proliferation and invasion of lung adenocarcinoma through the downregulation of peroxiredoxin 3.
Tumour Biol. 2016; 37(7):9781-8 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
In this study, we found the expression of Dachshund 1 (DACH1) is downregulated while peroxiredoxin 3 (PRX3) upregulated in both lung adenocarcinoma tissues and cells. Transfection of DACH1 can significantly downregulate PRX3 expression in targeting lung adenocarcinoma cells. Further experimental results demonstrated the evidence that overexpression of DACH1 resulted in significant retardation of in vitro proliferation and invasion of lung adenocarcinoma cells. Direct upregulation of PRX3 by co-transfection of PRX3 messenger RNA (mRNA) can prevent the above alteration caused by DACH1 transfection. Besides, lower DACH1 expression significantly correlated with tumor diameter and tumor invasion in all the 36 patients diagnosed with lung adenocarcinoma in our hospital during the past months. In conclusion, DACH1 can inhibit the proliferation and invasion of lung adenocarcinoma through the downregulation of PRX3. Decreased expression of DACH1 is involved in the initiation and development of lung cancer, which might be an adverse prognostic factor of lung adenocarcinoma.

Mullapudi N, Ye B, Suzuki M, et al.
Genome Wide Methylome Alterations in Lung Cancer.
PLoS One. 2015; 10(12):e0143826 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)-non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16). Further, when DM was coupled to differential transcriptome (DE) in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR) DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents.

Thomsen KG, Lyng MB, Elias D, et al.
Gene expression alterations associated with outcome in aromatase inhibitor-treated ER+ early-stage breast cancer patients.
Breast Cancer Res Treat. 2015; 154(3):483-94 [PubMed] Related Publications
Aromatase inhibitors (AI), either alone or together with chemotherapy, have become the standard adjuvant treatment for postmenopausal, estrogen receptor-positive (ER+) breast cancer. Although AIs improve overall survival, resistance is still a major clinical problem, thus additional biomarkers predictive of outcome of ER+ breast cancer patients treated with AIs are needed. Global gene expression analysis was performed on ER+ primary breast cancers from patients treated with adjuvant AI monotherapy; half experienced recurrence (median follow-up 6.7 years). Gene expression alterations were validated by qRT-PCR, and functional studies evaluating the effect of siRNA-mediated gene knockdown on cell growth were performed. Twenty-six genes, including TFF3, DACH1, RGS5, and GHR, were shown to exhibit altered expression in tumors from patients with recurrence versus non-recurrent (fold change ≥1.5, p < 0.05), and the gene expression alterations were confirmed using qRT-PCR. Ten of these 26 genes could be linked in a network associated with cellular proliferation, growth, and development. TFF3, which encodes for trefoil factor 3 and is an estrogen-responsive oncogene shown to play a functional role in tamoxifen resistance and metastasis of ER+ breast cancer, was also shown to be upregulated in an AI-resistant cell line model, and reduction of TFF3 levels using TFF3-specific siRNAs decreased the growth of both the AI-resistant and -sensitive parental cell lines. Moreover, overexpression of TFF3 in parental AI-sensitive MCF-7/S0.5 cells resulted in reduced sensitivity to the AI exemestane, whereas TFF3 overexpression had no effect on growth in the absence of exemestane, indicating that TFF3 mediates growth and survival signals that abrogate the growth inhibitory effect of exemestane. We identified a panel of 26 genes exhibiting altered expression associated with disease recurrence in patients treated with adjuvant AI monotherapy, including TFF3, which was shown to exhibit a growth- and survival-promoting effect in the context of AI treatment.

Majchrzak-Celińska A, Słocińska M, Barciszewska AM, et al.
Wnt pathway antagonists, SFRP1, SFRP2, SOX17, and PPP2R2B, are methylated in gliomas and SFRP1 methylation predicts shorter survival.
J Appl Genet. 2016; 57(2):189-97 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
The deregulation of Wnt signaling is observed in various cancers, including gliomas, and might be related to the methylation of the genes encoding antagonists of this signaling pathway. The aim of the study was to assess the methylation status of the promoter regions of six Wnt negative regulators and to determine their prognostic value in clinical samples of gliomas of different grades. The methylation of SFRP1, SFRP2, PPP2R2B, DKK1, SOX17, and DACH1 was analyzed in 64 glioma samples using methylation-specific polymerase chain reaction (MSP). The results were analyzed in correlation with clinicopathological data. Promoter methylation in at least one of the analyzed genes was found in 81.3 % of the tumors. All benign tumors [grade I according to the World Health Organization (WHO) classification] lacked the methylation of the studied genes, whereas grade II, III, and IV tumors were, in most cases, methylation-positive. The methylation index correlated with the patient's age. The most frequently methylated genes were SFRP1 and SFRP2 (73.4 % and 46.9 %, respectively), followed by SOX17 (20.3 %) and PPP2R2B (10.9 %); DKK1 and DACH1 were basically unmethylated (1.6 %). SFRP1 methylation negatively correlated with patients' survival time, and was significantly more frequent in older patients and those with higher grade tumors. Overall, the results of this study indicate that aberrant promoter methylation of Wnt pathway antagonists is common in gliomas, which may be the possible cause of up-regulation of this signaling pathway often observed in these tumors. Moreover, SFRP1 promoter methylation can be regarded as a potential indicator of glioma patients' survival.

Liu Y, Han N, Zhou S, et al.
The DACH/EYA/SIX gene network and its role in tumor initiation and progression.
Int J Cancer. 2016; 138(5):1067-75 [PubMed] Related Publications
The functional abnormality of developmental genes is a common phenomenon in cancer initiation and progression. The retinal determination gene network (RDGN) is a key signal in Drosophila eye specification, and this conservative pathway is also required for the development of multiple organs in mammalian species. Recent studies demonstrated that aberrant expressions of RDGN components in vertebrates, mainly Dach, Six, and Eya, represent a novel tumor signal. RDGN regulates proliferation, apoptosis, tumor growth and metastasis through interactions with multiple signaling pathways in a co-ordinated fashion; Dach acts as a tumor suppressor, whereas Six and Eya function as oncogenes. Clinical analyses demonstrated that the expression levels of RDGN correlate with tumor stage, metastasis and survival, suggesting that combinational detection of this pathway might be used as a promising biomarker for the stratification of therapy and for the prediction of the prognosis of cancer patients.

Liu Y, Zhou R, Yuan X, et al.
DACH1 is a novel predictive and prognostic biomarker in hepatocellular carcinoma as a negative regulator of Wnt/β-catenin signaling.
Oncotarget. 2015; 6(11):8621-34 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
The cell fate determination factor Dachshund (DACH1) functions as a novel suppressor in the progression of various neoplasms. Previous study has suggested that hypermethylation of promoter region was responsible for the reduction of DACH1 expression in hepatocellular carcinoma (HCC), and associated with the progression of HCC, but the clinical significance and the exact molecular mechanisms of DACH1 in the progression of HCC remain unclear. In this study, we employed public microarray data analysis and tissue microarrays (TMAs) technologies and showed that DACH1 expression was reduced in HCC even at early stage and associated with the tumor progression. Notably, Kaplan-Meier analysis further indicated DACH1 could be an independent prognostic factor for the overall survival of HCC. Further, mechanistic studies revealed that overexpression of DACH1 inhibited the growth and migration of HCC cell line, which were dependent in part on the inactivation of Wnt pathway via phosphorylation of GSK3β to suppress β-catenin. In agreement, the abundance of DACH1 was inversely correlated with several Wnt target genes. Collectively, our study indicated β-catenin is a novel target of DACH1 in HCC.

Han N, Yuan X, Wu H, et al.
DACH1 inhibits lung adenocarcinoma invasion and tumor growth by repressing CXCL5 signaling.
Oncotarget. 2015; 6(8):5877-88 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
Whole-genome and transcriptome sequencing of non-small cell lung cancer (NSCLC) identified that DACH1, is a human homolog of drosophila gene dac, is involved in NSCLC. Here we showed that expression of DACH1 was significantly decreased in human NSCLC tissues and DACH1 abundance was inversely correlated with tumor stages and grades. Restoration of DACH1 expression in NSCLC cells significantly reduced cellular proliferation, clone formation, migration and invasion in vitro, as well as tumor growth in vivo. Unbiased screen and functional study suggested that DACH1 mediated effects were dependent in part on suppression of CXCL5. There was an inverse correlation between DACH1 mRNA levels and CXCL5 in both lung cancer cell lines and human NSCLC tissues. Kaplan-Mier analysis of human NSCLC samples demonstrated that high DACH1 mRNA levels predicted favorable prognosis for relapse-free and overall survival. In agreement, high CXCL5 expression predicted a worse prognosis for survival.

Zhou J, Shaikh LH, Neogi SG, et al.
DACH1, a zona glomerulosa selective gene in the human adrenal, activates transforming growth factor-β signaling and suppresses aldosterone secretion.
Hypertension. 2015; 65(5):1103-10 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
Common somatic mutations in CACNAID and ATP1A1 may define a subgroup of smaller, zona glomerulosa (ZG)-like aldosterone-producing adenomas. We have therefore sought signature ZG genes, which may provide insight into the frequency and pathogenesis of ZG-like aldosterone-producing adenomas. Twenty-one pairs of zona fasciculata and ZG and 14 paired aldosterone-producing adenomas from 14 patients with Conn's syndrome and 7 patients with pheochromocytoma were assayed by the Affymetrix Human Genome U133 Plus 2.0 Array. Validation by quantitative real-time polymerase chain reaction was performed on genes >10-fold upregulated in ZG (compared with zona fasciculata) and >10-fold upregulated in aldosterone-producing adenomas (compared with ZG). DACH1, a gene associated with tumor progression, was further analyzed. The role of DACH1 on steroidogenesis, transforming growth factor-β, and Wnt signaling activity was assessed in the human adrenocortical cell line, H295R. Immunohistochemistry confirmed selective expression of DACH1 in human ZG. Silencing of DACH1 in H295R cells increased CYP11B2 mRNA levels and aldosterone production, whereas overexpression of DACH1 decreased aldosterone production. Overexpression of DACH1 in H295R cells activated the transforming growth factor-β and canonical Wnt signaling pathways but inhibited the noncanonical Wnt signaling pathway. Stimulation of primary human adrenal cells with angiotensin II decreased DACH1 mRNA expression. Interestingly, there was little overlap between our top ZG genes and those in rodent ZG. In conclusion, (1) the transcriptome profile of human ZG differs from rodent ZG, (2) DACH1 inhibits aldosterone secretion in human adrenals, and (3) transforming growth factor-β signaling pathway is activated in DACH1 overexpressed cells and may mediate inhibition of aldosterone secretion in human adrenals.

Chen K, Wu K, Jiao X, et al.
The endogenous cell-fate factor dachshund restrains prostate epithelial cell migration via repression of cytokine secretion via a cxcl signaling module.
Cancer Res. 2015; 75(10):1992-2004 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
Prostate cancer is the second leading form of cancer-related death in men. In a subset of prostate cancer patients, increased chemokine signaling IL8 and IL6 correlates with castrate-resistant prostate cancer (CRPC). IL8 and IL6 are produced by prostate epithelial cells and promote prostate cancer cell invasion; however, the mechanisms restraining prostate epithelial cell cytokine secretion are poorly understood. Herein, the cell-fate determinant factor DACH1 inhibited CRPC tumor growth in mice. Using Dach1(fl/fl)/Probasin-Cre bitransgenic mice, we show IL8 and IL6 secretion was altered by approximately 1,000-fold by endogenous Dach1. Endogenous Dach1 is shown to serve as a key endogenous restraint to prostate epithelial cell growth and restrains migration via CXCL signaling. DACH1 inhibited expression, transcription, and secretion of the CXCL genes (IL8 and IL6) by binding to their promoter regulatory regions in chromatin. DACH1 is thus a newly defined determinant of benign and malignant prostate epithelium cellular growth, migration, and cytokine abundance in vivo.

Paluszczak J, Sarbak J, Kostrzewska-Poczekaj M, et al.
The negative regulators of Wnt pathway-DACH1, DKK1, and WIF1 are methylated in oral and oropharyngeal cancer and WIF1 methylation predicts shorter survival.
Tumour Biol. 2015; 36(4):2855-61 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
The deregulation of Wnt signaling has recently emerged as one of the drivers of head and neck cancers. This is frequently related to the methylation of several antagonists of this pathway. This study aimed at the assessment of the profile of methylation of Wnt pathway antagonists and the determination of the prognostic value of the methylation of selected genes in oral carcinomas. The methylation of DACH1, DKK1, LKB1, PPP2R2B, RUNX3, SFRP2, and WIF-1 was analyzed in 16 oral squamous cell carcinoma cell lines using the methylation-specific polymerase chain reaction. The methylation of selected genes was further analyzed in tumor sections from 43 primary oral carcinoma patients. The analysis of oral carcinoma cell lines showed very frequent methylation of SFRP2 and WIF-1 and also a less frequent methylation of DACH1 and DKK1. On the other hand, RUNX3 was methylated only in one cell line, while LKB1 and PPP2R2B were not methylated in any of the cell lines. The biallelic methylation of DKK1 correlated with the low level of expression of this gene. Further evaluation of the methylation of DACH1, DKK1, and WIF1 in a clinical patient group confirmed the frequent methylation of WIF1 and intermediate or low frequency of methylation of DACH1 or DKK1, respectively. Importantly, the methylation of WIF-1 correlated with shorter survival in oral cancer patients. Overall, the methylation of the antagonists of Wnt pathway is frequently detected in oral squamous cell carcinomas. The methylation of WIF1 may be considered a prognostic marker in oral cancers.

Cohen H, Ben-Hamo R, Gidoni M, et al.
Shift in GATA3 functions, and GATA3 mutations, control progression and clinical presentation in breast cancer.
Breast Cancer Res. 2014; 16(6):464 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
INTRODUCTION: GATA binding protein 3 (GATA3) is a regulator of mammary luminal cell differentiation, and an estrogen receptor (ER) associated marker in breast cancer. Tumor suppressor functions of GATA3 have been demonstrated primarily in basal-like breast cancers. Here, we focused on its function in luminal breast cancer, where GATA3 is frequently mutated, and its levels are significantly elevated.
METHODS: GATA3 target genes were identified in normal- and luminal cancer- mammary cells by ChIP-seq, followed by examination of the effects of GATA3 expressions and mutations on tumorigenesis-associated genes and processes. Additionally, mutations and expression data of luminal breast cancer patients from The Cancer Genome Atlas were analyzed to characterize genetic signatures associated with GATA3 mutations.
RESULTS: We show that some GATA3 effects shift from tumor suppressing to tumor promoting during tumorigenesis, with deregulation of three genes, BCL2, DACH1, THSD4, representing major GATA3-controlled processes in cancer progression. In addition, we identify an altered activity of mutant GATA3, and distinct associated genetic signatures. These signatures depend on the functional domain mutated; and, for a specific subgroup, are shared with basal-like breast cancer patients, who are a clinical group with regard to considerations of mode of treatment.
CONCLUSIONS: The GATA3 dependent mechanisms may call for special considerations for proper prognosis and treatment of patients.

Chu Q, Han N, Yuan X, et al.
DACH1 inhibits cyclin D1 expression, cellular proliferation and tumor growth of renal cancer cells.
J Hematol Oncol. 2014; 7:73 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
BACKGROUND: Renal cell carcinoma (RCC) is a complex with diverse biological characteristics and distinct molecular signature. New target therapies to molecules that drive RCC initiation and progression have achieved promising responses in some patients, but the total effective rate is still far from satisfaction. Dachshund (DACH1) network is a key signaling pathway for kidney development and has recently been identified as a tumor suppressor in several cancer types. However, its role in renal cell carcinoma has not been fully investigated.
METHODS: Immunohistochemical staining for DACH1, PCNA and cyclin D1 was performed on human renal tissue microarrays and correlation with clinic-pathological characteristics was analyzed. In vitro proliferation, apoptosis and in vivo tumor growth were evaluated on human renal cancer cell lines with decitabine treatment or ectopic expression of DACH1. Downstream targets and potential molecular mechanism were investigated through western blot, immunoprecipitation and reporter gene assays.
RESULTS: Expression of DACH1 was significantly decreased in human renal carcinoma tissue. DACH1 protein abundance was inversely correlated with the expression of PCNA and cyclin D1, tumor grade, and TNM stage. Restoration of DACH1 function in renal clear cell cancer cells inhibited in vitro cellular proliferation, S phase progression, clone formation, and in vivo tumor growth. In mechanism, DACH1 repressed cyclin D1 transcription through association with AP-1 protein.
CONCLUSION: Our results indicated that DACH1 was a novel molecular marker of RCC and it attributed to the malignant behavior of renal cancer cells. Re-activation of DACH1 may represent a potential therapeutic strategy.

Yan W, Wu K, Herman JG, et al.
Epigenetic silencing of DACH1 induces the invasion and metastasis of gastric cancer by activating TGF-β signalling.
J Cell Mol Med. 2014; 18(12):2499-511 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
Gastric cancer (GC) is the fourth most common malignancy in males and the fifth most common malignancy in females worldwide. DACH1 is frequently methylated in hepatic and colorectal cancer. To further understand the regulation and mechanism of DACH1 in GC, eight GC cell lines, eight cases of normal gastric mucosa, 98 cases of primary GC and 50 cases of adjacent non-tumour tissues were examined. Methylation-specific PCR, western blot, transwell assay and xenograft mice were used in this study. Loss of DACH1 expression correlated with promoter region methylation in GC cells, and re-expression was induced by 5-Aza-2'-deoxyazacytidine. DACH1 is methylated in 63.3% (62/98) of primary GC and 38% (19/50) of adjacent non-tumour tissues, while no methylation was found in normal gastric mucosa. Methylation of DACH1 correlated with reduced expression of DACH1 (P < 0.01), late tumour stage (stage III/IV) (P < 0.01) and lymph node metastasis (P < 0.05). DACH1 expression inhibited epithelial-mesenchymal transition and metastasis by inhibiting transforming growth factor (TGF)-β signalling and suppressed GC cell proliferation through inducing G2/M phase arrest. The tumour size is smaller in DACH1-expressed BGC823 cell xenograft mice than in unexpressed group (P < 0.01). Restoration of DACH1 expression also sensitized GC cells to docetaxel. These studies suggest that DACH1 is frequently methylated in human GC and expression of DACH1 was controlled by promoter region methylation. DACH1 suppresses GC proliferation, invasion and metastasis by inhibiting TGF-β signalling pathways both in vitro and in vivo. Epigenetic silencing DACH1 may induce GC cells' resistance to docetaxel.

Elias D, Vever H, Lænkholm AV, et al.
Gene expression profiling identifies FYN as an important molecule in tamoxifen resistance and a predictor of early recurrence in patients treated with endocrine therapy.
Oncogene. 2015; 34(15):1919-27 [PubMed] Related Publications
To elucidate the molecular mechanisms of tamoxifen resistance in breast cancer, we performed gene array analyses and identified 366 genes with altered expression in four unique tamoxifen-resistant (TamR) cell lines vs the parental tamoxifen-sensitive MCF-7/S0.5 cell line. Most of these genes were functionally linked to cell proliferation, death and control of gene expression, and include FYN, PRKCA, ITPR1, DPYD, DACH1, LYN, GBP1 and PRLR. Treatment with FYN-specific small interfering RNA or a SRC family kinase inhibitor reduced cell growth of TamR cell lines while exerting no significant effect on MCF-7/S0.5 cells. Moreover, overexpression of FYN in parental tamoxifen-sensitive MCF-7/S0.5 cells resulted in reduced sensitivity to tamoxifen treatment, whereas knockdown of FYN in the FYN-overexpressing MCF-7/S0.5 cells restored sensitivity to tamoxifen, demonstrating growth- and survival-promoting function of FYN in MCF-7 cells. FYN knockdown in TamR cells led to reduced phosphorylation of 14-3-3 and Cdc25A, suggesting that FYN, by activation of important cell cycle-associated proteins, may overcome the anti-proliferative effects of tamoxifen. Evaluation of the subcellular localization of FYN in primary breast tumors from two cohorts of endocrine-treated ER+ breast cancer patients, one with advanced disease (N=47) and the other with early disease (N=76), showed that in the former, plasma membrane-associated FYN expression strongly correlated with longer progression-free survival (P<0.0002). Similarly, in early breast cancer patients, membrane-associated expression of FYN in the primary breast tumor was significantly associated with increased metastasis-free (P<0.04) and overall (P<0.004) survival independent of tumor size, grade or lymph node status. Our results indicate that FYN has an important role in tamoxifen resistance, and its subcellular localization in breast tumor cells may be an important novel biomarker of response to endocrine therapy in breast cancer.

Wu L, Herman JG, Brock MV, et al.
Silencing DACH1 promotes esophageal cancer growth by inhibiting TGF-β signaling.
PLoS One. 2014; 9(4):e95509 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
Human Dachshund homologue 1 (DACH1) is a major component of the Retinal Determination Gene Network. Loss of DACH1 expression was found in breast, prostate, lung, endometrial, colorectal and hepatocellular carcinoma. To explore the expression, regulation and function of DACH1 in human esophageal cancer, 11 esophageal cancer cell lines, 10 cases of normal esophageal mucosa, 51 cases of different grades of dysplasia and 104 cases of primary esophageal squamous cancer were employed. Methylation specific PCR, immunohistochemistry, western blot, flow cytometry, small interfering RNAs, colony formation techniques and xenograft mice model were used. We found that DACH1 expression was regulated by promoter region hypermethylation in esophageal cancer cell lines. 18.8% (6 of 32) of grade 1, 42.1% (8 of 19) of grade 2 and grade 3 dysplasia (ED2,3), and 61.5% (64 of 104) of esophageal cancer were methylated, but no methylation was found in 10 cases of normal esophageal mucosa. The methylation was increased in progression tendency during esophageal carcinogenesis (P<0.01). DACH1 methylation was associated with poor differentiation (P<0.05) and late tumor stage (P<0.05). Restoration of DACH1 expression inhibited cell growth and activated TGF-β signaling in KYSE150 and KYSE510 cells. DACH1 suppressed human esophageal cancer cell tumor growth in xenograft mice. In conclusion, DACH1 is frequently methylated in human esophageal cancer and methylation of DACH1 is involved in the early stage of esophageal carcinogenesis. DACH1 expression is regulated by promoter region hypermethylation. DACH1 suppresses esophageal cancer growth by activating TGF-β signaling.

Vonlanthen J, Okoniewski MJ, Menigatti M, et al.
A comprehensive look at transcription factor gene expression changes in colorectal adenomas.
BMC Cancer. 2014; 14:46 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
BACKGROUND: Biological processes are controlled by transcription networks. Expression changes of transcription factor (TF) genes in precancerous lesions are therefore crucial events in tumorigenesis. Our aim was to obtain a comprehensive picture of these changes in colorectal adenomas.
METHODS: Using a 3-pronged selection procedure, we analyzed transcriptomic data on 34 human tissue samples (17 adenomas and paired samples of normal mucosa, all collected with ethics committee approval and written, informed patient consent) to identify TFs with highly significant tumor-associated gene expression changes whose potential roles in colorectal tumorigenesis have been under-researched. Microarray data were subjected to stringent statistical analysis of TF expression in tumor vs. normal tissues, MetaCore-mediated identification of TF networks displaying enrichment for genes that were differentially expressed in tumors, and a novel quantitative analysis of the publications examining the TF genes' roles in colorectal tumorigenesis.
RESULTS: The 261 TF genes identified with this procedure included DACH1, which plays essential roles in the proper proliferation and differentiation of retinal and leg precursor cell populations in Drosophila melanogaster. Its possible roles in colorectal tumorigenesis are completely unknown, but it was found to be markedly overexpressed (mRNA and protein) in all colorectal adenomas and in most colorectal carcinomas. However, DACH1 expression was absent in some carcinomas, most of which were DNA mismatch-repair deficient. When networks were built using the set of TF genes identified by all three selection procedures, as well as the entire set of transcriptomic changes in adenomas, five hub genes (TGFB1, BIRC5, MYB, NR3C1, and TERT) where identified as putatively crucial components of the adenomatous transformation process.
CONCLUSION: The transcription-regulating network of colorectal adenomas (compared with that of normal colorectal mucosa) is characterized by significantly altered expression of over 250 TF genes, many of which have never been investigated in relation to colorectal tumorigenesis.

Fortschegger K, Anderl S, Denk D, Strehl S
Functional heterogeneity of PAX5 chimeras reveals insight for leukemia development.
Mol Cancer Res. 2014; 12(4):595-606 [PubMed] Related Publications
UNLABELLED: PAX5, a transcription factor pivotal for B-cell commitment and maintenance, is one of the most frequent targets of somatic mutations in B-cell precursor acute lymphoblastic leukemia. A number of PAX5 rearrangements result in the expression of in-frame fusion genes encoding chimeric proteins, which at the N-terminus consistently retain the PAX5 DNA-binding paired domain fused to the C-terminal domains of a markedly heterogeneous group of fusion partners. PAX5 fusion proteins are thought to function as aberrant transcription factors, which antagonize wild-type PAX5 activity. To gain mechanistic insight into the role of PAX5 fusion proteins in leukemogenesis, the biochemical and functional properties of uncharacterized fusions: PAX5-DACH1, PAX5-DACH2, PAX5-ETV6, PAX5-HIPK1, and PAX5-POM121 were ascertained. Independent of the subcellular distribution of the wild-type partner proteins, ectopic expression of all PAX5 fusion proteins showed a predominant nuclear localization, and by chromatin immunoprecipitation all of the chimeric proteins exhibited binding to endogenous PAX5 target sequences. Furthermore, consistent with the presence of potential oligomerization motifs provided by the partner proteins, the self-interaction capability of several fusion proteins was confirmed. Remarkably, a subset of the PAX5 fusion proteins conferred CD79A promoter activity; however, in contrast with wild-type PAX5, the fusion proteins were unable to induce Cd79a transcription in a murine plasmacytoma cell line. These data show that leukemia-associated PAX5 fusion proteins share some dominating characteristics such as nuclear localization and DNA binding but also show distinctive features.
IMPLICATIONS: This comparative study of multiple PAX5 fusion proteins demonstrates both common and unique properties, which likely dictate their function and impact on leukemia development.

Zhang J, Zhao CY, Zhang SH, et al.
Upregulation of miR-194 contributes to tumor growth and progression in pancreatic ductal adenocarcinoma.
Oncol Rep. 2014; 31(3):1157-64 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of human cancer worldwide. In the present study, we investigated the diagnostic and biological significance of microRNA-194 (miR-194) in PDAC. miRNA expression profiling of human PDACs and adjacent normal pancreatic tissues identified a total of 16 genes including miR-194 with >1.15-fold expression changes (8 overexpressed and 8 underexpressed). Quantitative real-time polymerase chain reaction (PCR) revealed elevation of serum miR-194 levels were significantly greater in PDAC patients than in duodenal adenocarcinoma patients and healthy controls. Receiver operating characteristic analysis demonstrated that serum miR-194 had a sensitivity of 54.3% and a specificity of 57.5% for discriminating PDAC patients from healthy controls. Combined analysis of the 3 groups yielded a sensitivity of 84.0 and a specificity of 75.0% for the combined detection of miR-192 and miR-194 in the diagnosis of PDAC. Ectopic expression of miR-194 in PANC-1 pancreatic cancer cells enhanced cell proliferation, migration and colony formation, which was coupled with decreased expression of the tumor suppressor DACH1. miR-194 overexpression increased tumor growth and local invasion and suppressed the expression of DACH1 in an orthotopic pancreatic cancer mouse model. In conclusion, upregulation of miR-194 contributes to tumor growth and progression in PDAC, possibly through suppression of DACH1. However, serum miR-194 has a low capacity for detection of PDAC. Combined detection of serum miR-192 and miR-194 levels may serve as a sensitive diagnostic biomarker for PDAC.

Powe DG, Dhondalay GK, Lemetre C, et al.
DACH1: its role as a classifier of long term good prognosis in luminal breast cancer.
PLoS One. 2014; 9(1):e84428 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
BACKGROUND: Oestrogen receptor (ER) positive (luminal) tumours account for the largest proportion of females with breast cancer. Theirs is a heterogeneous disease presenting clinical challenges in managing their treatment. Three main biological luminal groups have been identified but clinically these can be distilled into two prognostic groups in which Luminal A are accorded good prognosis and Luminal B correlate with poor prognosis. Further biomarkers are needed to attain classification consensus. Machine learning approaches like Artificial Neural Networks (ANNs) have been used for classification and identification of biomarkers in breast cancer using high throughput data. In this study, we have used an artificial neural network (ANN) approach to identify DACH1 as a candidate luminal marker and its role in predicting clinical outcome in breast cancer is assessed.
MATERIALS AND METHODS: A reiterative ANN approach incorporating a network inferencing algorithm was used to identify ER-associated biomarkers in a publically available cDNA microarray dataset. DACH1 was identified in having a strong influence on ER associated markers and a positive association with ER. Its clinical relevance in predicting breast cancer specific survival was investigated by statistically assessing protein expression levels after immunohistochemistry in a series of unselected breast cancers, formatted as a tissue microarray.
RESULTS: Strong nuclear DACH1 staining is more prevalent in tubular and lobular breast cancer. Its expression correlated with ER-alpha positive tumours expressing PgR, epithelial cytokeratins (CK)18/19 and 'luminal-like' markers of good prognosis including FOXA1 and RERG (p<0.05). DACH1 is increased in patients showing longer cancer specific survival and disease free interval and reduced metastasis formation (p<0.001). Nuclear DACH1 showed a negative association with markers of aggressive growth and poor prognosis.
CONCLUSION: Nuclear DACH1 expression appears to be a Luminal A biomarker predictive of good prognosis, but is not independent of clinical stage, tumour size, NPI status or systemic therapy.

Wu K, Chen K, Wang C, et al.
Cell fate factor DACH1 represses YB-1-mediated oncogenic transcription and translation.
Cancer Res. 2014; 74(3):829-39 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
The epithelial-mesenchymal transition (EMT) enhances cellular invasiveness and confers tumor cells with cancer stem cell-like characteristics, through transcriptional and translational mechanisms. The mechanisms maintaining transcriptional and translational repression of EMT and cellular invasion are poorly understood. Herein, the cell fate determination factor Dachshund (DACH1), suppressed EMT via repression of cytoplasmic translational induction of Snail by inactivating the Y box-binding protein (YB-1). In the nucleus, DACH1 antagonized YB-1-mediated oncogenic transcriptional modules governing cell invasion. DACH1 blocked YB-1-induced mammary tumor growth and EMT in mice. In basal-like breast cancer, the reduced expression of DACH1 and increased YB-1 correlated with poor metastasis-free survival. The loss of DACH1 suppression of both cytoplasmic translational and nuclear transcriptional events governing EMT and tumor invasion may contribute to poor prognosis in basal-like forms of breast cancer, a relatively aggressive disease subtype.

Yan W, Wu K, Herman JG, et al.
Epigenetic regulation of DACH1, a novel Wnt signaling component in colorectal cancer.
Epigenetics. 2013; 8(12):1373-83 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
Colorectal cancer (CRC) is one of the common malignant tumors worldwide. Both genetic and epigenetic changes are regarded as important factors of colorectal carcinogenesis. Loss of DACH1 expression was found in breast, prostate, and endometrial cancer. To analyze the regulation and function of DACH1 in CRC, 5 colorectal cancer cell lines, 8 cases of normal mucosa, 15 cases of polyps and 100 cases of primary CRC were employed in this study. In CRC cell lines, loss of DACH1 expression was correlated with promoter region hypermethylation, and re-expression of DACH1 was induced by 5-Aza-2'-deoxyazacytidine treatment. We found that DACH1 was frequently methylated in primary CRC and this methylation was associated with reduction in DACH1 expression. These results suggest that DACH1 expression is regulated by promoter region hypermethylation in CRC. DACH1 methylation was associated with late tumor stage, poor differentiation, and lymph node metastasis. Re-expression of DACH1 reduced TCF/LEF luciferase reporter activity and inhibited the expression of Wnt signaling downstream targets (c-Myc and cyclinD1). In xenografts of HCT116 cells in which DACH1 was re-expressed, tumor size was smaller than in controls. In addition, restoration of DACH1 expression induced G2/M phase arrest and sensitized HCT116 cells to docetaxel. DACH1 suppresses CRC growth by inhibiting Wnt signaling both in vitro and in vivo. Silencing of DACH1 expression caused resistance of CRC cells to docetaxel. In conclusion, DACH1 is frequently methylated in human CRC and methylation of DACH1 may serve as detective and prognostic marker in CRC.

Chen K, Wu K, Gormley M, et al.
Acetylation of the cell-fate factor dachshund determines p53 binding and signaling modules in breast cancer.
Oncotarget. 2013; 4(6):923-35 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
Breast cancer is a leading form of cancer in the world. The Drosophila Dac gene was cloned as an inhibitor of the hyperactive epidermal growth factor (EGFR), ellipse. Herein, endogenous DACH1 co-localized with p53 in a nuclear, extranucleolar compartment and bound to p53 in human breast cancer cell lines, p53 and DACH1 bound common genes in Chip-Seq. Full inhibition of breast cancer contact-independent growth by DACH1 required p53. The p53 breast cancer mutants R248Q and R273H, evaded DACH1 binding. DACH1 phosphorylation at serine residue (S439) inhibited p53 binding and phosphorylation at p53 amino-terminal sites (S15, S20) enhanced DACH1 binding. DACH1 binding to p53 was inhibited by NAD-dependent deacetylation via DACH1 K628. DACH1 repressed p21CIP1 and induced RAD51, an association found in basal breast cancer. DACH1 inhibits breast cancer cellular growth in an NAD and p53-dependent manner through direct protein-protein association.

Zhu H, Wu K, Yan W, et al.
Epigenetic silencing of DACH1 induces loss of transforming growth factor-β1 antiproliferative response in human hepatocellular carcinoma.
Hepatology. 2013; 58(6):2012-22 [PubMed] Related Publications
UNLABELLED: Human dachshund homolog 1 (DACH1) is a major component of the Retinal Determination Gene Network (RDGN) and functions as a tumor suppressor. However, the regulation of DACH1 expression and its function in hepatocellular carcinoma (HCC) remain unclear. In this study, epigenetic changes of DACH1 were analyzed in HCC cell lines and primary cancers. We found that promoter region hypermethylation was correlated with loss or reduction of DACH1 expression, and restoration of DACH1 expression was induced by 5-aza-2'-deoxycytidine (5-AZA) in HCC cell lines. Promoter region methylation was found in 42% of primary HCC. Reduced expression of DACH1 was associated with poor differentiation of HCC nodules and higher serum aspartate aminotransferase/alanine aminotransferase ratio. DACH1 suppressed cellular growth by reactivating transforming growth factor beta (TGF-β) signaling. Ectopic expression of DACH1 enhanced chemosensitivity to 5-fluorouracil (5-FU) by inducing p21 expression in HCC cells.
CONCLUSION: DACH1 is frequently methylated in HCC and DACH1 expression is regulated by promoter hypermethylation. Down-regulation of DACH1 is a novel mechanism for gaining resistance to the antiproliferative signaling of TGF-β1 and 5-FU resistance.

Chen K, Wu K, Cai S, et al.
Dachshund binds p53 to block the growth of lung adenocarcinoma cells.
Cancer Res. 2013; 73(11):3262-74 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
Hyperactive EGF receptor (EGFR) and mutant p53 are common genetic abnormalities driving the progression of non-small cell lung cancer (NSCLC), the leading cause of cancer deaths in the world. The Drosophila gene Dachshund (Dac) was originally cloned as an inhibitor of hyperactive EGFR alleles. Given the importance of EGFR signaling in lung cancer etiology, we examined the role of DACH1 expression in lung cancer development. DACH1 protein and mRNA expression was reduced in human NSCLC. Reexpression of DACH1 reduced NSCLC colony formation and tumor growth in vivo via p53. Endogenous DACH1 colocalized with p53 in a nuclear, extranucleolar location, and shared occupancy of -15% of p53-bound genes in ChIP sequencing. The C-terminus of DACH1 was necessary for direct p53 binding, contributing to the inhibition of colony formation and cell-cycle arrest. Expression of the stem cell factor SOX2 was repressed by DACH1, and SOX2 expression was inversely correlated with DACH1 in NSCLC. We conclude that DACH1 binds p53 to inhibit NSCLC cellular growth.

Govindan R, Ding L, Griffith M, et al.
Genomic landscape of non-small cell lung cancer in smokers and never-smokers.
Cell. 2012; 150(6):1121-34 [PubMed] Article available free on PMC after 24/06/2017 Related Publications
We report the results of whole-genome and transcriptome sequencing of tumor and adjacent normal tissue samples from 17 patients with non-small cell lung carcinoma (NSCLC). We identified 3,726 point mutations and more than 90 indels in the coding sequence, with an average mutation frequency more than 10-fold higher in smokers than in never-smokers. Novel alterations in genes involved in chromatin modification and DNA repair pathways were identified, along with DACH1, CFTR, RELN, ABCB5, and HGF. Deep digital sequencing revealed diverse clonality patterns in both never-smokers and smokers. All validated EFGR and KRAS mutations were present in the founder clones, suggesting possible roles in cancer initiation. Analysis revealed 14 fusions, including ROS1 and ALK, as well as novel metabolic enzymes. Cell-cycle and JAK-STAT pathways are significantly altered in lung cancer, along with perturbations in 54 genes that are potentially targetable with currently available drugs.

Lee JW, Kim HS, Hwang J, et al.
Regulation of HOXA9 activity by predominant expression of DACH1 against C/EBPα and GATA-1 in myeloid leukemia with MLL-AF9.
Biochem Biophys Res Commun. 2012; 426(3):299-305 [PubMed] Related Publications
Although MLL-AF9 caused by the chromosomal translocation t(9;11) has a critical role in acute myeloid leukemia, the molecular pathogenesis is poorly understood. Here, we identified that the cell fate determination factor DACH1 is directly up-regulated by MLL-AF9. Recently we showed that the forced expression of DACH1 in myeloid cells induced p27(Kip1) and repressed p21(Cip1), which is a pivotal characteristic of the myeloid progenitor. Consistent with our previous study, ectopic expression of DACH1 contributed to the maintenance of colonogenic activity and blocked the differentiation of myeloid progenitors. Moreover, we here identified an endogenous HOXA9-DACH1 complex mediated by the carboxyl terminus of DACH1 in t(9;11) leukemia cells. qRT-PCR revealed that DACH1 has a stronger transcription-promoting activity with HOXA9 than does PBX2 with HOXA9. Furthermore, C/EBPα and GATA-1 can directly bind to the promoter of DACH1 and act as a transcriptional suppressor. Expression of DACH1 is down-regulated during myeloid differentiation and shows an inverse pattern compared to C/EBPα and GATA-1 expression. However, ectopic expression of C/EBPα and/or GATA-1 could not abrogate the over-expression of DACH1 induced by MLL-AF9. Therefore, we postulate that the inability of C/EBPα and GATA-1 to down-regulate DACH1 expression induced by MLL-AF9 during myeloid differentiation may contribute to t(9;11) leukemogenesis.

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