The protein encoded by this gene is a member of the homeodomain family of DNA binding proteins. It may regulate gene expression, morphogenesis, and differentiation and it may also play a role in the cell cycle progession. Several alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Feb 2011]
CUX1 is implicated in: - auditory receptor cell differentiation
- chromatin binding
- Golgi membrane
- integral to Golgi membrane
- intra-Golgi vesicle-mediated transport
- lung development
- multicellular organismal development
- negative regulation of transcription from RNA polymerase II promoter
- protein binding, bridging
- regulation of transcription from RNA polymerase II promoter
- retrograde transport, vesicle recycling within Golgi
- sequence-specific DNA binding
- sequence-specific DNA binding transcription factor activity
- transcription, DNA-dependent
Data from Gene Ontology via CGAP [Hide]
CUX1 is a candidate tumour supressor gene. A study from the Sanger Institute (Wong CC et al. Nature Genetivs, 2013) used genetic data from over 7,600 cancer patients, collected and sequenced by the International Cancer Genome Constortium (ICGC) and other groups. They found that CUX1 is mutated at a relatively low frequency, but across many different types of cancer. The study found that when CUX1 is deactivated, it had a knock-on effect on a biological inhibitor, PIK3IP1, reducing its inhibitory effects. This mobilises an enzyme responsible for cell growth, phosphoinositide 3-kinase (PI3K), increasing the rate of tumour progression.
Wong CC et al, Nature Genetics 2013 Study "[interrogated] the genomes of 7,651 diverse human cancers and find inactivating mutations in the homeodomain transcription factor gene CUX1...Meta-analysis of CUX1 mutational status in 2,519 cases of myeloid malignancies reveals disruptive mutations associated with poor survival, highlighting the clinical significance of CUX1 loss."
CUX1 OMIM, Johns Hopkin University Referenced article focusing on the relationship between phenotype and genotype.
CUX1 International Cancer Genome Consortium. Summary of gene and mutations by cancer type from ICGC
CUX1 Cancer Genome Anatomy Project, NCI Gene Summary
CUX1 COSMIC, Sanger Institute Somatic mutation information and related details
CUX1 GEO Profiles, NCBI Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Fibroblast growth factor (FGF)2, FGF4, FGF7 and FGF20 are representative paracrine FGFs binding to heparan-sulfate proteoglycan and fibroblast growth factor receptors (FGFRs), whereas FGF19, FGF21 and FGF23 are endocrine FGFs binding to Klotho and FGFRs. FGFR1 is relatively frequently amplified and overexpressed in breast and lung cancer, and FGFR2 in gastric cancer. BCR-FGFR1, CNTRL-FGFR1, CUX1-FGFR1, FGFR1OP-FGFR1, MYO18A-FGFR1 and ZMYM2-FGFR1 fusions in myeloproliferative neoplasms are non-receptor-type FGFR kinases, whereas FGFR1-TACC1, FGFR2-AFF3, FGFR2-BICC1, FGFR2-PPHLN1, FGFR3-BAIAP2L1 and FGFR3-TACC3 fusions in solid tumors are transmembrane-type FGFRs with C-terminal alterations. AZD4547, BGJ398 (infigratinib), Debio-1347 and dovitinib are FGFR1/2/3 inhibitors; BLU9931 is a selective FGFR4 inhibitor; FIIN-2, JNJ-42756493, LY2874455 and ponatinib are pan-FGFR inhibitors. AZD4547, dovitinib and ponatinib are multi-kinase inhibitors targeting FGFRs, colony stimulating factor 1 receptor (CSF1R), vascular endothelial growth factor (VEGF)R2, and others. The tumor microenvironment consists of cancer cells and stromal/immune cells, such as cancer-associated fibroblasts (CAFs), endothelial cells, M2-type tumor-associating macrophages (M2-TAMs), myeloid-derived suppressor cells (MDSCs) and regulatory T cells. FGFR inhibitors elicit antitumor effects directly on cancer cells, as well as indirectly through the blockade of paracrine signaling. The dual inhibition of FGF and CSF1 or VEGF signaling is expected to enhance the antitumor effects through the targeting of immune evasion and angiogenesis in the tumor microenvironment. Combination therapy using tyrosine kinase inhibitors (FGFR or CSF1R inhibitors) and immune checkpoint blockers (anti-PD-1 or anti-CTLA-4 monoclonal antibodies) may be a promising choice for cancer patients. The inhibition of FGF19-FGFR4 signaling is associated with a risk of liver toxicity, whereas the activation of FGF23-FGFR4 signaling is associated with a risk of heart toxicity. Endocrine FGF signaling affects the pathophysiology of cancer patients who are prescribed FGFR inhibitors. Whole-genome sequencing is necessary for the detection of promoter/enhancer alterations of FGFR genes and rare alterations of other genes causing FGFR overexpression. To sustain the health care system in an aging society, a benefit-cost analysis should be performed with a focus on disease-free survival and the total medical cost before implementing genome-based precision medicine for cancer patients.
Fibroids represent a major public health care problem as the most prevalent pelvic tumors in women of reproductive age and as the leading cause of gynecologic surgeries in the United States. The recent advances in the genomic technologies including genome-wide association studies and high-throughput sequencing provide insight into their pathogenesis and molecular classification. Understanding the molecular basis of fibroids may facilitate development of effective targeted treatment options of this very common disease.
Ding Z, Yang HW, Xia TS, et al. Integrative genomic analyses of the RNA-binding protein, RNPC1, and its potential role in cancer prediction. Int J Mol Med. 2015; 36(2):473-84 [PubMed] Related Publications
The RNA binding motif protein 38 (RBM38, also known as RNPC1) plays a pivotal role in regulating a wide range of biological processes, from cell proliferation and cell cycle arrest to cell myogenic differentiation. It was originally recognized as an oncogene, and was frequently found to be amplified in prostate, ovarian and colorectal cancer, chronic lymphocytic leukemia, colon carcinoma, esophageal cancer, dog lymphomas and breast cancer. In the present study, the complete RNPC1 gene was identified in a number of vertebrate genomes, suggesting that RNPC1 exists in all types of vertebrates, including fish, amphibians, birds and mammals. In the different genomes, the gene had a similar 4 exon/3 intron organization, and all the genetic loci were syntenically conserved. The phylogenetic tree demonstrated that the RNPC1 gene from the mammalian, bird, reptile and teleost lineage formed a species-specific cluster. A total of 34 functionally relevant single nucleotide polymorphisms (SNPs), including 14 SNPs causing missense mutations, 8 exonic splicing enhancer SNPs and 12 SNPs causing nonsense mutations, were identified in the human RNPC1 gene. RNPC1 was found to be expressed in bladder, blood, brain, breast, colorectal, eye, head and neck, lung, ovarian, skin and soft tissue cancer. In 14 of the 94 tests, an association between RNPC1 gene expression and cancer prognosis was observed. We found that the association between the expression of RNPC1 and prognosis varied in different types of cancer, and even in the same type of cancer from the different databases used. This suggests that the function of RNPC1 in these tumors may be multidimensional. The sex determining region Y (SRY)-box 5 (Sox5), runt-related transcription factor 3 (RUNX3), CCAAT displacement protein 1 (CUTL1), v-rel avian reticuloendotheliosis viral oncogene homolog (Rel)A, peroxisome proliferator-activated receptor γ isoform 2 (PPARγ2) and activating transcription factor 6 (ATF6) regulatory transcription factor binding sites were identified in the upstream (promoter) region of the RNPC1 gene, and may thus be involved in the effects of RNPC1 in tumors.
Nagel S, Ehrentraut S, Meyer C, et al. NFkB is activated by multiple mechanisms in hairy cell leukemia. Genes Chromosomes Cancer. 2015; 54(7):418-32 [PubMed] Related Publications
Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder of unclear pathogenesis. Recent studies have identified BRAF(V600E) mutations in most HCL patients, highlighting this abnormality as a molecular hallmark for this disease. Cell lines originating from HCL patients lack BRAF mutations but retain the typical piliferous morphology and the distinctive HCL immunophenotype, thus, constituting suitable tools for identifying alternative tumor genes and leukemic mechanisms in this malignancy. To this end, we integrated genomic and transcriptional profiling of the HCL cell line MLMA. The expression levels of genomically targeted genes were compared to four HCL control cell lines, thus, identifying 91 chromosomally deregulated genes. Gene set enrichment analysis of these indicted apoptosis, proliferation, and DNA damage response as altered processes. Accordingly, prominent target genes overexpressed in this cell line include ATM, BRAF, CDK6, CUTL1/CUX1, H2AFX, and REL. Treatment of MLMA with selective pharmacological inhibitors and specific siRNA-mediated gene knockdowns highlighted a central role for NFkB in their deregulation in HCL. Moreover, relevant expression profiling data from HCL and ABC-DLBCL cell lines display elevated NFkB-pathway activity when compared to GC-DLBCL equivalents. Finally, analysis of HCL patient samples in silico collectively supported the clinical significance of NFkB activation in this disease. In conclusion, we identified deregulated genes and multiple mechanisms underlying aberrantly activated NFkB-pathway in HCL. Therefore, NFkB may represent a B-cell specific hallmark of HCL and a promising novel therapeutic target, most notably in patients lacking BRAF mutations in this entity including variant HCL.
Schwarzer A, Holtmann H, Brugman M, et al. Hyperactivation of mTORC1 and mTORC2 by multiple oncogenic events causes addiction to eIF4E-dependent mRNA translation in T-cell leukemia. Oncogene. 2015; 34(27):3593-604 [PubMed] Related Publications
High activation of the PI3K-AKT-mTOR pathway is characteristic for T-cell acute lymphoblastic leukemia (T-ALL). The activity of the master regulator of this pathway, PTEN, is often impaired in T-ALL. However, experimental evidence suggests that input from receptor tyrosine kinases (RTKs) is required for sustained mTOR activation, even in the absence of PTEN. We previously reported the expression of Neurotrophin receptor tyrosine kinases (TRKs) and their respective ligands in primary human leukemia samples. In the present study we aimed to dissect the downstream signaling cascades of TRK-induced T-ALL in a murine model and show that T-ALLs induced by deregulated receptor tyrosine kinase signaling acquire activating mutations in Notch1 and lose PTEN during clonal evolution. Some clones additionally lost one allele of the homeodomain transcription factor Cux1. All events independently led to a gradual hyperactivation of both mTORC1 and mTORC2 signaling. We dissected the role of the individual mTOR complexes by shRNA knockdown and found that the separate depletion of mTORC1 or mTORC2 reduced the growth of T-ALL blasts, but was not sufficient to induce apoptosis. In contrast, knockdown of the mTOR downstream effector eIF4E caused a striking cytotoxic effect, demonstrating a critical addiction to cap-dependent mRNA-translation. Although high mTORC2-AKT activation is commonly associated with drug-resistance, we demonstrate that T-ALL displaying a strong mTORC2-AKT activation were specifically susceptible to 4EGI-1, an inhibitor of the eIF4E-eIF4G interaction. To decipher the mechanism of 4EGI-1, we performed a genome-wide analysis of mRNAs that are translationally regulated by 4EGI-1 in T-ALL. 4EGI-1 effectively reduced the ribosomal occupancy of mRNAs that were strongly upregulated in T-ALL blasts compared with normal thymocytes including transcripts important for translation, mitochondria and cell cycle progression, such as cyclins and ribosomal proteins. These data suggest that disrupting the eIF4E-eIF4G interaction constitutes a promising therapy strategy in mTOR-deregulated T-cell leukemia.
Ramdzan ZM, Nepveu A CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers. Nat Rev Cancer. 2014; 14(10):673-82 [PubMed] Related Publications
CUT-like homeobox 1 (CUX1) is a homeobox gene that is implicated in both tumour suppression and progression. The accumulated evidence supports a model of haploinsufficiency whereby reduced CUX1 expression promotes tumour development. Paradoxically, increased CUX1 expression is associated with tumour progression, and ectopic CUX1 expression in transgenic mice increases tumour burden in several tissues. One CUX1 isoform functions as an ancillary factor in base excision repair and the other CUX1 isoforms act as transcriptional activators or repressors. Several transcriptional targets and cellular functions of CUX1 affect tumorigenesis; however, we have yet to develop a mechanistic framework to reconcile the opposite roles of CUX1 in cancer protection and progression.
Mehine M, Mäkinen N, Heinonen HR, et al. Genomics of uterine leiomyomas: insights from high-throughput sequencing. Fertil Steril. 2014; 102(3):621-9 [PubMed] Related Publications
Uterine leiomyomas are benign smooth-muscle tumors of extremely low malignant potential. Early work utilizing classical cytogenetics revealed that a subset of uterine leiomyomas harbor recurrent chromosomal rearrangements, such as translocations affecting the HMGA2 gene. Our understanding of the genetics of many tumor types has deepened remarkably with the emergence of next-generation sequencing technologies. Exome sequencing identified that the majority of leiomyomas display highly specific MED12 mutations. Further studies suggest that these MED12 hotspot mutations are also frequent in breast fibroadenomas, but not in other human tumors. Whole-genome sequencing showed that a subset of leiomyomas display complex chromosomal rearrangements resembling chromothripsis. These were formed in a single event of chromosomal breakage and random reassembly involving one or a limited number of chromosomes. Although most leiomyomas have been shown to arise independently, these studies also revealed that distinct nodules within a uterus may display identical genetic changes indicating a common clonal origin. A minority of leiomyomas were also found to display deletions within the COL4A5-COL4A6 genes, leading to upregulation of the adjacent gene IRS4. The findings derived from high-throughput sequencing combined with previous knowledge have led to an emerging molecular classification of leiomyomas, suggesting that there are several distinct pathogenic pathways involved in leiomyoma formation. The evidence points to at least 4 molecular subclasses: leiomyomas with MED12 mutation, FH inactivation, HMGA2 overexpression, and COL4A6-COL4A5 deletion. Elucidating the molecular pathogenesis of leiomyomas should be relevant for developing treatments for this very common disease.
Topka S, Glassmann A, Weisheit G, et al. The transcription factor Cux1 in cerebellar granule cell development and medulloblastoma pathogenesis. Cerebellum. 2014; 13(6):698-712 [PubMed] Related Publications
Cux1, also known as Cutl1, CDP or Cut is a homeodomain transcription factor implicated in the regulation of normal and oncogenic development in diverse peripheral tissues and organs. We studied the expression and functional role of Cux1 in cerebellar granule cells and medulloblastoma. Cux1 is robustly expressed in proliferating granule cell precursors and in postmitotic, migrating granule cells. Expression is lost as postmigratory granule cells mature. Moreover, Cux1 is also strongly expressed in a well-established mouse model of medulloblastoma. In contrast, expression of CUX1 in human medulloblastoma tissue samples is lower than in normal fetal cerebellum. In these tumors, CUX1 expression tightly correlates with a set of genes which, when mapped on a global protein-protein interaction dataset, yields a tight network that constitutes a cell cycle control signature and may be related to p53 and the DNA damage response pathway. Antisense-mediated reduction of CUX1 levels in two human medulloblastoma cell lines led to a decrease in proliferation and altered motility. The developmental expression of Cux1 in the cerebellum and its action in cell lines support a role in granule cell and medulloblastoma proliferation. Its expression in human medulloblastoma shifts that perspective, suggesting that CUX1 is part of a network involved in cell cycle control and maintenance of DNA integrity. The constituents of this network may be rational targets to therapeutically approach medulloblastomas.
McNerney ME, Brown CD, Peterson AL, et al. The spectrum of somatic mutations in high-risk acute myeloid leukaemia with -7/del(7q). Br J Haematol. 2014; 166(4):550-6 [PubMed] Related Publications
-7/del(7q) occurs in half of myeloid malignancies with adverse-risk cytogenetic features and is associated with poor survival. We identified the spectrum of mutations that co-occur with -7/del(7q) in 40 patients with de novo or therapy-related myeloid neoplasms. -7/del(7q) leukaemias have a distinct mutational profile characterized by low frequencies of alterations in genes encoding transcription factors, cohesin and DNA-methylation-related proteins. In contrast, RAS pathway activating mutations occurred in 50% of cases, a significantly higher frequency than other acute myeloid leukaemias and higher than previously reported. Our data provide guidance for which pathways may be most relevant in the treatment of adverse-risk myeloid leukaemia.
The Cut homeobox 1 (CUX1) gene is a target of loss-of-heterozygosity in many cancers, yet elevated CUX1 expression is frequently observed and is associated with shorter disease-free survival. The dual role of CUX1 in cancer is illustrated by the fact that most cell lines with CUX1 LOH display amplification of the remaining allele, suggesting that decreased CUX1 expression facilitates tumor development while increased CUX1 expression is needed in tumorigenic cells. Indeed, CUX1 was found in a genome-wide RNAi screen to identify synthetic lethal interactions with oncogenic RAS. Here we show that CUX1 functions in base excision repair as an ancillary factor for the 8-oxoG-DNA glycosylase, OGG1. Single cell gel electrophoresis (comet assay) reveals that Cux1⁺/⁻ MEFs are haploinsufficient for the repair of oxidative DNA damage, whereas elevated CUX1 levels accelerate DNA repair. In vitro base excision repair assays with purified components demonstrate that CUX1 directly stimulates OGG1's enzymatic activity. Elevated reactive oxygen species (ROS) levels in cells with sustained RAS pathway activation can cause cellular senescence. We show that elevated expression of either CUX1 or OGG1 prevents RAS-induced senescence in primary cells, and that CUX1 knockdown is synthetic lethal with oncogenic RAS in human cancer cells. Elevated CUX1 expression in a transgenic mouse model enables the emergence of mammary tumors with spontaneous activating Kras mutations. We confirmed cooperation between Kras(G12V) and CUX1 in a lung tumor model. Cancer cells can overcome the antiproliferative effects of excessive DNA damage by inactivating a DNA damage response pathway such as ATM or p53 signaling. Our findings reveal an alternate mechanism to allow sustained proliferation in RAS-transformed cells through increased DNA base excision repair capability. The heightened dependency of RAS-transformed cells on base excision repair may provide a therapeutic window that could be exploited with drugs that specifically target this pathway.
Nakao K, Miyaaki H, Ichikawa T Antitumor function of microRNA-122 against hepatocellular carcinoma. J Gastroenterol. 2014; 49(4):589-93 [PubMed] Related Publications
MicroRNA-122 (miR-122), a highly abundant and liver-specific miRNA, acts as a tumor suppressor against hepatocellular carcinoma (HCC). Decreased expression of miR-122 in HCC is frequently observed and is associated with poor differentiation, larger tumor size, metastasis and invasion, and poor prognosis. Mutant mice with knockout (KO) of the miR-122 locus developed steatohepatitis due to increased triglyceride (TG) synthesis and decreased TG secretion from hepatocytes, and eventually developed HCC. Exogenic miR-122 introduction into miR-122 KO mice inhibited the development of HCC. Target genes of miR-122, including cyclin G1, a disintegrin and metalloprotease (ADAM)10, serum response factor, insulin-like growth factor-1 receptor, ADAM17, transcription factor CUTL1, the embryonic isoform of pyruvate kinase (Pkm2), Wnt1, pituitary tumor-transforming gene 1 binding factor, Cut-like homeobox 1, and c-myc, are involved in hepatocarcinogenesis, epithelial mesenchymal transition, and angiogenesis. MiR-122 expression is regulated by liver-enriched transcription factors such as hepatocyte nuclear factor (HNF)1α, HNF3β, HNF4α, HNF6, and CCAAT/enhancer-binding protein (C/EBP)α. A positive feedback loop exists between C/EBPα and miR-122 and between HNF6 and miR-122, whereas a negative feedback loop exists between c-myc and miR-122. Since cotreatment of 5-Aza-Cd and histone deacetylase inhibitor restored miR-122 expression in HCC cells, epigenetic modulation of miR-122 expression is involved in the suppression of miR-122 in HCC. Several experiments suggest that increasing miR-122 levels in HCC with or without antitumor agents may be a promising strategy for HCC treatment.
Lira ME, Choi YL, Lim SM, et al. A single-tube multiplexed assay for detecting ALK, ROS1, and RET fusions in lung cancer. J Mol Diagn. 2014; 16(2):229-43 [PubMed] Related Publications
Approximately 7% of non-small cell lung carcinomas (NSCLCs) harbor oncogenic fusions involving ALK, ROS1, and RET. Although tumors harboring ALK fusions are highly sensitive to crizotinib, emerging preclinical and clinical data demonstrate that patients with ROS1 or RET fusions may also benefit from inhibitors targeting these kinases. Using a transcript-based method, we designed a combination of 3' overexpression and fusion-specific detection strategies to detect ALK, ROS1 and RET fusion transcripts in NSCLC tumors. We validated the assay in 295 NSCLC specimens and showed that the assay is highly sensitive and specific. ALK results were 100% concordant with fluorescence in situ hybridization (FISH) (n = 52) and 97.8% concordant with IHC (n = 179) [sensitivity, 96.8% (95% CI 91.0%-98.9%); specificity, 98.8% (95% CI 93.6%-99.8%)]. For ROS1 and RET, we also observed 100% concordance with FISH (n = 46 and n = 15, respectively). We identified seven ROS1 and 14 RET fusion-positive tumors and confirmed the fusion status by RT-PCR and FISH. One RET fusion involved a novel partner, cutlike homeobox 1 gene (CUX1), yielding an in-frame CUX1-RET fusion. ROS1 and RET fusions were significantly enriched in tumors without KRAS/EGFR/ALK alterations. ALK/ROS1/RET/EGFR/KRAS alterations were mutually exclusive. As a single-tube assay, this test shows promise as a more practical and cost-effective screening modality for detecting rare but targetable fusions in NSCLC.
A major challenge in cancer genetics is to determine which low-frequency somatic mutations are drivers of tumorigenesis. Here we interrogate the genomes of 7,651 diverse human cancers and find inactivating mutations in the homeodomain transcription factor gene CUX1 (cut-like homeobox 1) in ~1-5% of various tumors. Meta-analysis of CUX1 mutational status in 2,519 cases of myeloid malignancies reveals disruptive mutations associated with poor survival, highlighting the clinical significance of CUX1 loss. In parallel, we validate CUX1 as a bona fide tumor suppressor using mouse transposon-mediated insertional mutagenesis and Drosophila cancer models. We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. Thus, our complementary approaches identify CUX1 as a pan-driver of tumorigenesis and uncover a potential strategy for treating CUX1-mutant tumors.
Bian J, Li B, Zeng X, et al. Mutation of TGF-β receptor II facilitates human bladder cancer progression through altered TGF-β1 signaling pathway. Int J Oncol. 2013; 43(5):1549-59 [PubMed] Related Publications
Tumor cells commonly adapt survival strategies by downregulation or mutational inactivation of TGF-β receptors thereby reversing TGF-β1-mediated growth arrest. However, TGF-β1-triggered signaling also has a protumor effect through promotion of tumor cell migration. The mechanism(s) through which malignant cells reconcile this conflict by avoiding growth arrest, but strengthening migration remains largely unclear. TGF-βRII was overexpressed in the bladder cancer cell line T24, concomitant with point mutations, especially the Glu269 to Lys mutation (G → A). Whilst leaving Smad2/3 binding unaffected, TGF-βRII mutations resulted in the unaffected tumor cell growth and also enhanced cell mobility by TGF-β1 engagement. Such phenomena are perhaps partially explained by the mutated TGF-βRII pathway deregulating the p15 and Cdc25A genes that are important to cell proliferation and CUTL1 gene relevant to motility. On the other hand, transfecting recombinant TGF-βRII-Fc vectors or smad2/3 siRNA blocked such abnormal gene expressions. Clinically, such G → A mutations were also found in 18 patients (n=46) with bladder cancer. Comparing the clinical and pathologic characteristics, the pathologic T category (χ2 trend = 7.404, P<0.01) and tumor grade (χ2 trend = 9.127, P<0.01) tended to increase in the G → A mutated group (TGF-βRII point-mutated group). These findings provide new insights into how TGF-β1 signaling is tailored during tumorigenesis and new information into the current TGF-β1-based therapeutic strategies, especially in bladder cancer patient treatment.
Loss of chromosome 7 and del(7q) [-7/del(7q)] are recurring cytogenetic abnormalities in hematologic malignancies, including acute myeloid leukemia and therapy-related myeloid neoplasms, and associated with an adverse prognosis. Despite intensive effort by many laboratories, the putative myeloid tumor suppressor(s) on chromosome 7 has not yet been identified.We performed transcriptome sequencing and SNP array analysis on de novo and therapy-related myeloid neoplasms, half with -7/del(7q). We identified a 2.17-Mb commonly deleted segment on chromosome band 7q22.1 containing CUX1, a gene encoding a homeodomain-containing transcription factor. In 1 case, CUX1 was disrupted by a translocation, resulting in a loss-of-function RNA fusion transcript. CUX1 was the most significantly differentially expressed gene within the commonly deleted segment and was expressed at haploinsufficient levels in -7/del(7q) leukemias. Haploinsufficiency of the highly conserved ortholog, cut, led to hemocyte overgrowth and tumor formation in Drosophila melanogaster. Similarly, haploinsufficiency of CUX1 gave human hematopoietic cells a significant engraftment advantage on transplantation into immunodeficient mice. Within the RNA-sequencing data, we identified a CUX1-associated cell cycle transcriptional gene signature, suggesting that CUX1 exerts tumor suppressor activity by regulating proliferative genes. These data identify CUX1 as a conserved, haploinsufficient tumor suppressor frequently deleted in myeloid neoplasms.
Liu KC, Lin BS, Zhao M, et al. Cutl1: a potential target for cancer therapy. Cell Signal. 2013; 25(1):349-54 [PubMed] Related Publications
CDP, a key transcription regulator encoded by Cutl1 gene, has been demonstrated to be involved in repressing or promoting expression of target genes through its specific DNA-binding, meanwhile, the activity of CDP was influenced by some types of modifications including transcriptional, posttranscriptional, translational and posttranslational modifications. In this review, we systematically analyzed the role of CDP in normal development and tumor progression, and then emphasized its interactors and downstream molecules. Eventually, we concluded that Cut1 could promote cancer progression and its down-regulating expression will be a promising strategy for cancer therapy.
Schoenmakers EF, Bunt J, Hermers L, et al. Identification of CUX1 as the recurrent chromosomal band 7q22 target gene in human uterine leiomyoma. Genes Chromosomes Cancer. 2013; 52(1):11-23 [PubMed] Related Publications
Uterine leiomyomas are benign solid tumors of mesenchymal origin which occur with an estimated incidence of up to 77% of all women of reproductive age. The majority of these tumors remains symptomless, but in about a quarter of cases they cause leiomyoma-associated symptoms including chronic pelvic pain, menorrhagia-induced anemia, and impaired fertility. As a consequence, they are the most common indication for pre-menopausal hysterectomy in the USA and Japan and annually translate into a multibillion dollar healthcare problem. Approximately 40% of these neoplasms present with recurring structural cytogenetic anomalies, including del(7)(q22), t(12;14)(q15;q24), t(1;2)(p36;p24), and anomalies affecting 6p21 and/or 10q22. Using positional cloning strategies, we and others previously identified HMGA1, HMGA2, RAD51L1, MORF, and, more recently, NCOA1 as primary target (fusion) genes associated with tumor initiation in four of these distinct cytogenetic subgroups. Despite the fact that the del(7)(q22) subgroup is the largest among leiomyomas, and was first described more than twenty years ago, the 7q22 leiomyoma target gene still awaits unequivocal identification. We here describe a positional cloning effort from two independent uterine leiomyomas, containing respectively a pericentric and a paracentric chromosomal inversion, both affecting band 7q22. We found that both chromosomal inversions target the cut-like homeobox 1 (CUX1) gene on chromosomal band 7q22.1 in a way which is functionally equivalent to the more frequently observed del(7q) cases, and which is compatible with a mono-allelic knock-out scenario, similar as was previously described for the cytogenetic subgroup showing chromosome 14q involvement.
Relle M, Becker M, Meyer RG, et al. Intronic promoters and their noncoding transcripts: a new source of cancer-associated genes. Mol Carcinog. 2014; 53(2):117-24 [PubMed] Related Publications
Recent studies of mammalian genomes suggest that alternative promoters are associated with various disorders, including cancer. Here we present an intronic promoter of the murine proteinase 3 gene, which drives the expression of an alternative mRNA in intron 2 of the prtn3 gene. The proximal promoter sequences were identified and a series of promoter deletion constructs were used to identify the sequence elements that are required for basal promoter activity. Expression of the homeobox transcription factor CUX1 p75 isoform was found to suppress the activity of the alternative PR3 promoter. Data base analyses, multiple alignments and expression data showed that the intronic PR3 promoter is active in leukemia and other tumor cells as well as in mouse embryo, male mammary gland and bone marrow. In the spleen, the transcript is exclusively expressed by Gr-1(int) /CD11b(+) cells, which are also known as myeloid-derived suppressor cells (MDSCs). In humans, an alternative transcript of the PR3-gene could be detected in the bone marrow and in various cancer cell lines but not in primary leukemia cells, suggesting a species-overarching function of this kind of promoter. Therefore, the alternative PR3 promoter and its mRNA may be useful tools to investigate the fate of hematopoietic stem cells.
Milosevic JD, Puda A, Malcovati L, et al. Clinical significance of genetic aberrations in secondary acute myeloid leukemia. Am J Hematol. 2012; 87(11):1010-6 [PubMed] Related Publications
The study aimed to identify genetic lesions associated with secondary acute myeloid leukemia (sAML) in comparison with AML arising de novo (dnAML) and assess their impact on patients' overall survival (OS). High-resolution genotyping and loss of heterozygosity mapping was performed on DNA samples from 86 sAML and 117 dnAML patients, using Affymetrix Genome-Wide Human SNP 6.0 arrays. Genes TP53, RUNX1, CBL, IDH1/2, NRAS, NPM1, and FLT3 were analyzed for mutations in all patients. We identified 36 recurrent cytogenetic aberrations (more than five events). Mutations in TP53, 9pUPD, and del7q (targeting CUX1 locus) were significantly associated with sAML, while NPM1 and FLT3 mutations associated with dnAML. Patients with sAML carrying TP53 mutations demonstrated lower 1-year OS rate than those with wild-type TP53 (14.3% ± 9.4% vs. 35.4% ± 7.2%; P = 0.002), while complex karyotype, del7q (CUX1) and del7p (IKZF1) showed no significant effect on OS. Multivariate analysis confirmed that mutant TP53 was the only independent adverse prognostic factor for OS in sAML (hazard ratio 2.67; 95% CI: 1.33-5.37; P = 0.006). Patients with dnAML and complex karyotype carried sAML-associated defects (TP53 defects in 54.5%, deletions targeting FOXP1 and ETV6 loci in 45.4% of the cases). We identified several co-occurring lesions associated with either sAML or dnAML diagnosis. Our data suggest that distinct genetic lesions drive leukemogenesis in sAML. High karyotype complexity of sAML patients does not influence OS. Somatic mutations in TP53 are the only independent adverse prognostic factor in sAML. Patients with dnAML and complex karyotype show genetic features associated with sAML and myeloproliferative neoplasms.
Zhai Z, Ha N, Papagiannouli F, et al. Antagonistic regulation of apoptosis and differentiation by the Cut transcription factor represents a tumor-suppressing mechanism in Drosophila. PLoS Genet. 2012; 8(3):e1002582 [PubMed] Free Access to Full ArticleRelated Publications
Apoptosis is essential to prevent oncogenic transformation by triggering self-destruction of harmful cells, including those unable to differentiate. However, the mechanisms linking impaired cell differentiation and apoptosis during development and disease are not well understood. Here we report that the Drosophila transcription factor Cut coordinately controls differentiation and repression of apoptosis via direct regulation of the pro-apoptotic gene reaper. We also demonstrate that this regulatory circuit acts in diverse cell lineages to remove uncommitted precursor cells in status nascendi and thereby interferes with their potential to develop into cancer cells. Consistent with the role of Cut homologues in controlling cell death in vertebrates, we find repression of apoptosis regulators by Cux1 in human cancer cells. Finally, we present evidence that suggests that other lineage-restricted specification factors employ a similar mechanism to put the brakes on the oncogenic process.
Hulea L, Nepveu A CUX1 transcription factors: from biochemical activities and cell-based assays to mouse models and human diseases. Gene. 2012; 497(1):18-26 [PubMed] Related Publications
ChIP-chip and expression analyses indicated that CUX1 transcription factors regulate a large number of genes and microRNAs involved in multiple cellular processes. Indeed, in proliferating cells CUX1 was shown to regulate several genes involved in DNA replication, progression into S phase and later, the spindle assembly checkpoint that controls progression through mitosis. siRNA-mediated knockdown established that CUX1 is required for cell motility. Moreover, higher expression of short CUX1 isoforms, as observed in many cancers, was shown to stimulate cell migration and invasion. In parallel, elevated expression particularly in higher grade tumors of breast and pancreatic cancers implicated CUX1 in tumor initiation and progression. Indeed, transgenic mouse models demonstrated a causal role of CUX1 in cancers originating from various cell types. These studies revealed that higher CUX1 expression or activity not only stimulates cell proliferation and motility, but also promotes genetic instability. CUX1 has also been implicated in the etiology of polycystic kidney diseases, both from a transgenic approach and the analysis of CUX1 activity in multiple mouse models of this disease. Studies in neurobiology have uncovered a potential implication of CUX1 in cognitive disorders, neurodegeneration and obesity. CUX1 was shown to be expressed specifically in pyramidal neurons of the neocortex upper layers where it regulates dendrite branching, spine development, and synapse formation. In addition, modulation of CUX1 expression in neurons of the hypothalamus has been associated with changes in leptin receptor trafficking in the vicinity of the primary cilium resulting in altered leptin signaling and ultimately, eating behavior. Overall, studies in various fields have allowed the development of several cell-based assays to monitor CUX1 function and have extended the range of organs in which CUX1 plays an important role in development and tissue homeostasis.
Kojima K, Takata A, Vadnais C, et al. MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma. Nat Commun. 2011; 2:338 [PubMed] Related Publications
α-fetoprotein (AFP) is not only a widely used biomarker in hepatocellular carcinoma (HCC) surveillance, but is also clinically recognized as linked with aggressive tumour behaviour. Here we show that deregulation of microRNA122, a liver-specific microRNA, is a cause of both AFP elevation and a more biologically aggressive phenotype in HCC. We identify CUX1, a direct target of microRNA122, as a common central mediator of these two effects. Using liver tissues from transgenic mice in which microRNA122 is functionally silenced, an orthotopic xenograft tumour model, and human clinical samples, we further demonstrate that a microRNA122/CUX1/microRNA214/ZBTB20 pathway regulates AFP expression. We also show that the microRNA122/CUX1/RhoA pathway regulates the aggressive characteristics of tumours. We conclude that microRNA122 and associated signalling proteins may represent viable therapeutic targets, and that serum AFP levels in HCC patients may be a surrogate marker for deregulated intracellular microRNA122 signalling pathways in HCC tissues.
Klampfl T, Harutyunyan A, Berg T, et al. Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression. Blood. 2011; 118(1):167-76 [PubMed] Related Publications
Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are clonal myeloid disorders with increased production of terminally differentiated cells. The disease course is generally chronic, but some patients show disease progression (secondary myelofibrosis or accelerated phase) and/or leukemic transformation. We investigated chromosomal aberrations in 408 MPN samples using high-resolution single-nucleotide polymorphism microarrays to identify disease-associated somatic lesions. Of 408 samples, 37.5% had a wild-type karyotype and 62.5% harbored at least 1 chromosomal aberration. We identified 25 recurrent aberrations that were found in 3 or more samples. An increased number of chromosomal lesions was significantly associated with patient age, as well as with disease progression and leukemic transformation, but no association was observed with MPN subtypes, Janus kinase 2 (JAK2) mutational status, or disease duration. Aberrations of chromosomes 1q and 9p were positively associated with disease progression to secondary myelofibrosis or accelerated phase. Changes of chromosomes 1q, 7q, 5q, 6p, 7p, 19q, 22q, and 3q were positively associated with post-MPN acute myeloid leukemia. We mapped commonly affected regions to single target genes on chromosomes 3p (forkhead box P1 [FOXP1]), 4q (tet oncogene family member 2 [TET2]), 7p (IKAROS family zinc finger 1 [IKZF1]), 7q (cut-like homeobox 1 [CUX1]), 12p (ets variant 6 [ETV6]), and 21q (runt-related transcription factor 1 [RUNX1]). Our data provide insight into the genetic complexity of MPNs and implicate new genes involved in disease progression.
Cell populations able to generate a large repertoire of genetic variants have increased potential to generate tumor cells that survive through the multiple selection steps involved in tumor progression. A mechanism for the generation of aneuploid cancer cells involves passage through a tetraploid stage. Supernumerary centrosomes, however, can lead to multipolar mitosis and cell death. Using tissue culture and transgenic mouse models of breast cancer, we report that Cut homeobox 1 (CUX1) causes chromosomal instability by activating a transcriptional program that prevents multipolar divisions and enables the survival of tetraploid cells that evolve to become genetically unstable and tumorigenic. Transcriptional targets of CUX1 involved in DNA replication and bipolar mitosis defined a gene expression signature that, across 12 breast cancer gene expression datasets, was associated with poor clinical outcome. The signature not only was higher in breast tumor subtypes of worse prognosis, like the basal-like and HER2(+) subtypes, but also identified poor outcome among estrogen receptor-positive/node-negative tumors, a subgroup considered to be at lower risk. The CUX1 signature therefore represents a unique criterion to stratify patients and provides insight into the molecular determinants of poor clinical outcome.
Fréchette I, Darsigny M, Brochu-Gaudreau K, et al. The Promyelocytic Leukemia Zinc Finger (PLZF ) gene is a novel transcriptional target of the CCAAT-Displacement-protein (CUX1) repressor. FEBS J. 2010; 277(20):4241-53 [PubMed] Related Publications
The CCAAT-Displacement-Protein (CUX1) can transcriptionally repress sucrase–isomaltase gene expression, a specific product of enterocytes that becomes re-expressed during human colonic polyposis. Little is known of the gene repertoire that is directly affected by CUX1 in the intestinal epithelial context. This article identifies the Promyelocytic Leukemia Zinc Finger (PLZF) gene as a transcriptional target for the CUX1 repressor. CUX1 interacts in vivo with multiple DNA-binding sites in the 5′-UTR and promoter of the PLZF gene in colorectal cancer cells, a region that is functionally targeted by CUX1 in cotransfection assays. PLZF was found to be induced in colorectal cancer cell lines, correlating with a low detectable level of CUX1, a pattern that was reversed in normal human colonocytes. Reduction of p200CUX1 expression by RNAi in the Caco-2/15 cell line increased PLZF gene transcript expression. Because of the implication of Plzf in the regulation of stem cell maintenance, as well as Wnt and Ras signaling, in other systems, our observations suggest that the novel genetic relationship between CUX1 and PLZF could be of relevance to human diseases, such as leukemia, and open up a new field of investigation for the implication of these regulators during intestinal polyposis and cancer.
Previously, we identified the transcription factor CUX1 as an important modulator of invasion and resistance to apoptosis. Expression profiles suggested that CUX1 regulates a complex transcriptional program mediating tumor progression. We aimed to identify functionally relevant targets of CUX1 by using RNA interference (RNAi)-based loss-of-function screens. Therefore, we generated an RNAi library containing putative transcriptional targets of CUX1 identified by microarrays and performed cell viability screens. Using this approach, several CUX1 targets with effect on tumor cell viability were identified, including the glutamate receptor GRIA3, which was validated in detail for its effects on proliferation, apoptosis, and cell migration using RNAi knock-down and overexpression strategies in vitro, as well as xenograft models in vivo. The expression of GRIA3 was evaluated in human pancreatic cancer tissues. We found that knock-down of GRIA3 significantly reduced proliferation and migration and enhanced apoptosis. In contrast, overexpression of GRIA3 significantly reduced apoptosis and enhanced both proliferation and tumor cell migration. GRIA3 could be confirmed as a downstream effector of CUX1 and was expressed in pancreatic cancer tissues. In vivo, GRIA3 significantly enhanced the growth of subcutaneous xenografts. Inhibitors of glutamate receptors such as GYKI52466 and SYM2206 significantly decreased survival of pancreatic cancer cells, suggesting the presence of glutamate signaling in pancreatic cancer. In conclusion, GRIA3 plays a role as a mediator of tumor progression in pancreatic cancer downstream CUX1. To our knowledge, this is the first report to identify a glutamate receptor as a modulator of tumor progression in a solid cancer outside the brain.
Ripka S, Neesse A, Riedel J, et al. CUX1: target of Akt signalling and mediator of resistance to apoptosis in pancreatic cancer. Gut. 2010; 59(8):1101-10 [PubMed] Related Publications
BACKGROUND AND AIMS: The transcription factor CUX1 is known as a regulator of cell differentiation and cell cycle progression. Previously, CUX1 was identified as a modulator of invasiveness in various cancers. Based on expression profiles suggesting a role for CUX1 in mediating chemoresistance, the aim of this study was to characterise the effect of CUX1 on apoptosis as well as its regulation by signalling pathways modulating drug resistance in pancreatic cancer. METHODS: The effect of CUX1 on TRAIL- (tumour necrosis factor-related apoptosis-inducing ligand) and drug-induced apoptosis was analysed using overexpression and knock-down strategies. Regulation of CUX1 by phosphatidylinositol-3-kinase (PI3K)/Akt signalling was examined at the mRNA and protein level. The effect of CUX1 knock-down by nanoparticle-complexed small interfering RNA (siRNA) in vivo was analysed in a murine xenograft model. Furthermore, CUX1 RNA and protein expression was evaluated in human pancreatic cancer and adjacent normal tissues. RESULTS: Knock-down of CUX1 resulted in significantly enhanced TRAIL- and drug-induced apoptosis, associated with increased PARP (poly ADP-ribose polymerase) cleavage and caspase activity. Vice versa, overexpression of CUX1 inhibited apoptosis. CUX1 expression was induced by activation of Akt/protein kinase B signalling, and decreased by PI3K inhibitors. The antiapoptotic effect of CUX1 was associated with upregulation of BCL2 and downregulation of tumour necrosis factor alpha. CUX1 was significantly overexpressed in pancreatic cancers, as analysed by in situ hybridisation and immunohistochemistry. In vivo, silencing of CUX1 by intratumourally administered polyethylenimine-complexed siRNA led to reduced tumour growth and increased apoptosis in pancreatic cancer xenografts. CONCLUSION: CUX1 was identified as an important mediator of tumour cell survival in pancreatic cancer in vitro and in vivo.
The Cut homeobox gene 1 (CUX1) codes for several homeodomain proteins that display distinct DNA binding and transcriptional properties. Some CUX1 isoforms were previously shown to stimulate entry into S phase. More recently, siRNA-mediated knockdown of CUX1 was shown to cause a decrease in cell migration and invasion. In contrast, ectopic expression of p110 or p75 CUX1 stimulated cell migration and invasion in tissue culture. Moreover, metastasis to the lung was observed in a few cases following development of mammary tumors in p75 CUX1 transgenic mice. Chromatin immunoprecipitation (ChIP) assays followed by hybridization on promoter arrays (ChIP-chip) led to the identification of more than 20 genes that are directly regulated by CUX1 and code for proteins involved in cytoskeleton remodeling, cell-cell and cell-matrix adhesion, epithelial to mesenchymal transition and transcriptional regulation. Many targets of CUX1 are regulators of Rho GTPases that play a role both in cell cycle progression and cell motility. Interestingly, some genes that promote cell motility are activated by CUX1, while some genes that inhibit cell motility are repressed by CUX1. The dual function of CUX1 as an activator and repressor is best exemplified by the regulatory cascade whereby CUX1 activates expression of the Snail and Slug transcription factors and then cooperates with them to repress the E-cadherin and occludin genes, thereby causing a severe disorganization of cell-cell junctions. Together, these studies indicate that CUX1 stimulates cell motility by regulating a large number of genes involved in various molecular functions.
Ochiai E, Kitagawa H, Takada I, et al. CDP/cut is an osteoblastic coactivator of the vitamin D receptor (VDR). J Bone Miner Res. 2010; 25(5):1157-66 [PubMed] Related Publications
Vitamin D plays an important role in regulating bone and calcium metabolism. The actions of vitamin D are mediated through the nuclear vitamin D receptor (VDR), and gene disruption of the VDR in mice causes skeletal disorders. However, the precise role of the VDR in each stage of osteoblastogenesis is not well understood. To address this issue, we used a biochemical approach to identify an osteoblast-specific coregulator of the VDR. Using a GST-fused VDR ligand-binding domain as bait, proteins associated with liganded VDR were purified from nuclear extracts of HOS osteoblastic cells and compared with those of HeLa cells. Among the interactants identified by mass fingerprinting, CCAAT displacement protein (CDP) was found as a novel ligand-dependent VDR interactant in HOS cells, together with other previously reported DRIP/TRAP complex components. Further biochemical analysis showed that complex formation between the VDR and CDP was distinct from the previously known DRIP/TRAP complex and the p160 family coactivator complexes. Transient expression of CDP potentiated VDR-mediated transcriptional activation in HOS cells. Furthermore, modulation of CDP expression levels in osteoblastic SaM-1 cells affected vitamin D-dependent osteoblast differentiation before the maturation (mineralization) stage. These findings suggest that CDP is a novel differentiation stage-specific coactivator of the VDR in osteoblasts.
Cadieux C, Kedinger V, Yao L, et al. Mouse mammary tumor virus p75 and p110 CUX1 transgenic mice develop mammary tumors of various histologic types. Cancer Res. 2009; 69(18):7188-97 [PubMed] Related Publications
The p75 and p110 isoforms of the CUX1 homeodomain protein are overexpressed in breast tumors and cancer cell lines. To assess and compare the ability of these short CUX1 isoforms in driving mammary tumor development, we used site-specific transgenesis into the Hprt locus to generate transgenic mice expressing p75 or p110 CUX1 under the control of the mouse mammary tumor virus-long terminal repeat. We report that mammary tumors developed after a long latency period, and although various histopathologies were observed, the proportion of adenosquamous carcinomas was significantly higher in p75 CUX1 than in p110 CUX1 transgenic mice. Metastasis to the lung was observed in three p75 CUX1 transgenic mice. Comparisons between tumors and adjacent normal mammary glands revealed that transgenes were overexpressed in most but not all tumors, yet in all cases tested, CUX1 DNA binding was increased, suggesting that both higher expression and changes in post-translational modifications can contribute to stimulate transgene activity. Interestingly, higher expression of erbB2 mRNA was seen in most tumors, not only solid carcinomas but also adenosquamous carcinomas, whereas higher expression of various Wnt genes and activation of the beta-catenin pathway was observed primarily in adenosquamous carcinomas. Activation of erbB2 expression appeared to represent a cooperating event that occurred independently of CUX1. In contrast, chromatin immunoprecipitation, short hairpin RNA-mediated knockdown, and reporter assays established that CUX1 is involved in the transcriptional regulation of several Wnt genes. Together, these results support the notion that oncogenic activity of CUX1 can facilitate the establishment of a Wnt/beta-catenin autocrine loop.
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Cite this page: Cotterill SJ. CUX1, Cancer Genetics Web: http://www.cancer-genetics.org/CUX1.htm Accessed: