Gene Summary

Gene:FUBP1; far upstream element (FUSE) binding protein 1
Aliases: FBP, FUBP, hDH V
Summary:The protein encoded by this gene is a single stranded DNA-binding protein that binds to multiple DNA elements, including the far upstream element (FUSE) located upstream of c-myc. Binding to FUSE occurs on the non-coding strand, and is important to the regulation of c-myc in undifferentiated cells. This protein contains three domains, an amphipathic helix N-terminal domain, a DNA-binding central domain, and a C-terminal transactivation domain that contains three tyrosine-rich motifs. The N-terminal domain is thought to repress the activity of the C-terminal domain. This protein is also thought to bind RNA, and contains 3'-5' helicase activity with in vitro activity on both DNA-DNA and RNA-RNA duplexes. Aberrant expression of this gene has been found in malignant tissues, and this gene is important to neural system and lung development. Binding of this protein to viral RNA is thought to play a role in several viral diseases, including hepatitis C and hand, foot and mouth disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:far upstream element-binding protein 1
Source:NCBIAccessed: 06 August, 2015


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

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: FUBP1 (cancer-related)

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.
N Engl J Med. 2015; 372(26):2481-98 [PubMed] Related Publications
BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas.
METHODS: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes.
RESULTS: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma.
CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).

Sheng H, Ying L, Zheng L, et al.
Down Expression of FBP1 Is a Negative Prognostic Factor for Non-Small-Cell Lung Cancer.
Cancer Invest. 2015; 33(5):197-204 [PubMed] Related Publications
Downregulation of fructose-1,6-bisphosphatse-1 (FBP1) was observed in several cancers but its role in the lung cancer still remains unknown. We examined the cancer tissues from 140 patients with nonsmall cell lung cancer patients and found that the relative gene expression of FBP1 was significantly lower in lung cancer tissues as compared to incisal marginal tissues and normal tissues. The patients with higher level of FBP1 RNA expression have significantly longer disease free survival and overall survival as compared to the lower expression groups. There was a negative correlation with the level of FBP1 and recurrence of the lung cancer.

Kumar A, Pathak P, Purkait S, et al.
Oncogenic KIAA1549-BRAF fusion with activation of the MAPK/ERK pathway in pediatric oligodendrogliomas.
Cancer Genet. 2015; 208(3):91-5 [PubMed] Related Publications
Pediatric oligodendrogliomas (pODGs) are rare central nervous system tumors, and comparatively little is known about their molecular pathogenesis. Co-deletion of 1p/19q; and IDH1, CIC, and FUBP1 mutations, which are molecular signatures of adult oligodendrogliomas, are extremely rare in pODGs. In this report, two pODGs, one each of grade II and grade III, were evaluated using clinical, radiological, histopathologic, and follow-up methods. IDH1, TP53, CIC, H3F3A, and BRAF-V600 E mutations were analyzed by Sanger sequencing and immunohistochemical methods, and 1p/19q co-deletion was analyzed by fluorescence in situ hybridization. PDGFRA amplification, BRAF gain, intragenic duplication of FGFR-TKD, and KIAA1549-BRAF fusion (validated by Sanger sequencing) were analyzed by real-time reverse transcription PCR. Notably, both cases showed the oncogenic KIAA1549_Ex15-BRAF_Ex9 fusion transcript. Further, immunohistochemical analysis showed activation of the MAPK/ERK pathway in both of these cases. However, neither 1p/19q co-deletion; IDH1, TP53, CIC, H3F3A, nor BRAF-V600 E mutation; PDGFRA amplification; BRAF gain; nor duplication of FGFR-TKD was identified. Overall, this study highlights that pODGs can harbor the KIAA1549-BRAF fusion with aberrant MAPK/ERK signaling, and there exists an option of targeting these pathways in such patients. These results indicate that pODGs with the KIAA1549-BRAF fusion may represent a subset of this rare tumor that shares molecular and genetic features of pilocytic astrocytomas. These findings will increase our understanding of pODGs and may have clinical implications.

Chen J, Lee HJ, Wu X, et al.
Gain of glucose-independent growth upon metastasis of breast cancer cells to the brain.
Cancer Res. 2015; 75(3):554-65 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Breast cancer brain metastasis is resistant to therapy and a particularly poor prognostic feature in patient survival. Altered metabolism is a common feature of cancer cells, but little is known as to what metabolic changes benefit breast cancer brain metastases. We found that brain metastatic breast cancer cells evolved the ability to survive and proliferate independent of glucose due to enhanced gluconeogenesis and oxidations of glutamine and branched chain amino acids, which together sustain the nonoxidative pentose pathway for purine synthesis. Silencing expression of fructose-1,6-bisphosphatases (FBP) in brain metastatic cells reduced their viability and improved the survival of metastasis-bearing immunocompetent hosts. Clinically, we showed that brain metastases from human breast cancer patients expressed higher levels of FBP and glycogen than the corresponding primary tumors. Together, our findings identify a critical metabolic condition required to sustain brain metastasis and suggest that targeting gluconeogenesis may help eradicate this deadly feature in advanced breast cancer patients.

Dixit U, Liu Z, Pandey AK, et al.
Fuse binding protein antagonizes the transcription activity of tumor suppressor protein p53.
BMC Cancer. 2014; 14:925 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: FUSE binding protein1 (FBP1) is a transactivator of transcription of human c-myc proto-oncogene and expressed mainly in undifferentiated cells. It is also present in differentiated normal cells albeit with very low background. FBP1 is abundantly expressed in the majority of hepatocellular carcinoma tumors and has been implicated in tumor development. Although it down-regulates the expression of proapoptotic p21 protein, it is not known whether FBP1 also interacts and antagonizes the function of tumor suppressor protein p53.
METHODS: Western blotting was carried out to detect the expression level of FBP1, p21 and p53, and also p53 regulatory factors, BCCIP and TCTP; real-time quantitative PCR was done to determine the fold change in mRNA levels of target proteins; immunoprecipitation was carried out to determine the interaction of FBP1 with p53, BCCIP and TCTP. Cells stably knockdown for either FBP1; p53 or BCCIP were examined for p53 reporter activity under normal and radiation-induced stress.
RESULTS: FBP1 physically interacted with p53, impairing its transcription activity and reducing p53-mediated sensitivity to cellular stress. Knockdown of FBP1 expression activated p53-mediated response to cellular stress while transient expression of FBP1 in FBP-knockdown cells restored the inhibition of p53 activity. FBP1 not only interacted with both BCCIP and TCTP, which, respectively, function as positive and negative regulators of p53, but also regulated their expression under cellular stress. In FBP knockdown cells, TCTP expression was down-regulated under radiation-induced stress whereas expression of BCCIP and p21 were significantly up-regulated suggesting FBP1 as a potential regulator of these proteins. We hypothesize that the FBP1-mediated suppression of p53 activity may occur via preventing the interaction of p53 with BCCIP as well as by FBP1-mediated regulation of p53 regulatory proteins, TCTP and BCCIP. Since FBP1 suppresses p53 activity and is overexpressed in most HCC tumors, it may have a possible role in tumorigenesis.
CONCLUSION: FBP1 physically interacts with p53, functions as a regulator of p53-regulatory proteins (TCTP and BCCIP), and suppresses p53 transactivation activity under radiation-induced cellular stress. Since it is abundantly expressed in most HCC tumors, it may have implication in tumorigenesis and thus may be a possible target for drug development.

Cohen AL, Colman H
Glioma biology and molecular markers.
Cancer Treat Res. 2015; 163:15-30 [PubMed] Related Publications
The tumors classified as gliomas include a wide variety of histologies including the more common (astrocytoma, glioblastoma), as well as the less common histologies (oligodendroglioma, mixed oligoastrocytoma, pilocytic astrocytoma). Recent efforts at comprehensive genetic characterization of various primary brain tumor types have identified a number of common alterations and pathways common to multiple tumor types. Common pathways in glioma biology include growth factor receptor tyrosine kinases and their downstream signaling via the MAP kinase cascade or PI3K signaling, loss of apoptosis through p53, cell cycle regulation, angiogenesis via VEGF signaling, and invasion. However, in addition to these common general pathway alterations, a number of specific alterations have been identified in particular tumor types, and a number of these have direct therapeutic implications. These include mutations or fusions in the BRAF gene seen in pilocytic astrocytomas (and gangliogliomas). In oligodendrogliomas, mutations in IDH1 and codeletion of chromosomes 1p and 19q are associated with improved survival with upfront use of combined chemotherapy and radiation, and these tumors also have unique mutations of CIC and FUBP1 genes. Low grade gliomas are increasingly seen to be divided into two groups based on IDH mutation status, with astrocytomas developing through IDH mutation followed by p53 mutation, while poor prognosis low grade gliomas and primary glioblastomas (GBMs) are characterized by EGFR amplification, loss of PTEN, and loss of cyclin-dependent kinase inhibitors. GBMs can be further characterized based on gene expression and gene methylation patterns into three or four distinct subgroups. Prognostic markers in diffuse gliomas include IDH mutation, 1p/19q codeletion, and MGMT methylation, and MGMT is also a predictive marker in elderly patients with glioblastoma treated with temozolomide monotherapy.

Appin CL, Brat DJ
Molecular pathways in gliomagenesis and their relevance to neuropathologic diagnosis.
Adv Anat Pathol. 2015; 22(1):50-8 [PubMed] Related Publications
Gliomas are a large and diverse group of primary brain tumors that include those that are diffusely infiltrative and others that are well-circumscribed and low grade. Diffuse gliomas are currently classified by the World Health Organization as astrocytomas, oligodendrogliomas, or oligoastrocytomas and range in grade from II to IV. Glioblastoma (GBM), World Health Organization grade IV, is the highest grade and most common form of astrocytoma. In the past, the diagnosis of gliomas was almost exclusively based on histopathologic features. More recently, improved understanding of molecular genetic underpinnings has led to ancillary molecular studies becoming standard for classification, prognostication, and predicting therapy response. Isocitrate dehydrogenase (IDH) mutations are frequent in grade II and III infiltrating gliomas and secondary GBMs. Infiltrating astrocytomas and secondary GBMs are characterized by IDH, TP53, and ATRX mutations, whereas oligodendrogliomas demonstrate 1p/19q codeletion and mutations in IDH, CIC, FUBP1, and the telomerase reverse transcriptase (TERT) promoter. Primary GBMs typically lack IDH mutations and are instead characterized by EGFR, PTEN, TP53, PDGFRA, NF1, and CDKN2A/B alterations and TERT promoter mutations. Pediatric GBMs differ from those in adults and frequently have mutations in H3F3A, ATRX, and DAXX, but not IDH. In contrast, circumscribed, low-grade gliomas of childhood, such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and ganglioglioma, often harbor mutations or activating gene rearrangements in BRAF. Neuropathologic assessment of gliomas increasingly relies on ancillary testing of molecular alterations for proper classification and patient management.

Pénzváltó Z, Lánczky A, Lénárt J, et al.
MEK1 is associated with carboplatin resistance and is a prognostic biomarker in epithelial ovarian cancer.
BMC Cancer. 2014; 14:837 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: Primary systemic treatment for ovarian cancer is surgery, followed by platinum based chemotherapy. Platinum resistant cancers progress/recur in approximately 25% of cases within six months. We aimed to identify clinically useful biomarkers of platinum resistance.
METHODS: A database of ovarian cancer transcriptomic datasets including treatment and response information was set up by mining the GEO and TCGA repositories. Receiver operator characteristics (ROC) analysis was performed in R for each gene and these were then ranked using their achieved area under the curve (AUC) values. The most significant candidates were selected and in vitro functionally evaluated in four epithelial ovarian cancer cell lines (SKOV-3-, CAOV-3, ES-2 and OVCAR-3), using gene silencing combined with drug treatment in viability and apoptosis assays. We collected 94 tumor samples and the strongest candidate was validated by IHC and qRT-PCR in these.
RESULTS: All together 1,452 eligible patients were identified. Based on the ROC analysis the eight most significant genes were JRK, CNOT8, RTF1, CCT3, NFAT2CIP, MEK1, FUBP1 and CSDE1. Silencing of MEK1, CSDE1, CNOT8 and RTF1, and pharmacological inhibition of MEK1 caused significant sensitization in the cell lines. Of the eight genes, JRK (p = 3.2E-05), MEK1 (p = 0.0078), FUBP1 (p = 0.014) and CNOT8 (p = 0.00022) also correlated to progression free survival. The correlation between the best biomarker candidate MEK1 and survival was validated in two independent cohorts by qRT-PCR (n = 34, HR = 5.8, p = 0.003) and IHC (n = 59, HR = 4.3, p = 0.033).
CONCLUSION: We identified MEK1 as a promising prognostic biomarker candidate correlated to response to platinum based chemotherapy in ovarian cancer.

Malz M, Bovet M, Samarin J, et al.
Overexpression of far upstream element (FUSE) binding protein (FBP)-interacting repressor (FIR) supports growth of hepatocellular carcinoma.
Hepatology. 2014; 60(4):1241-50 [PubMed] Related Publications
UNLABELLED: The far upstream element binding protein (FBP) and the FBP-interacting repressor (FIR) represent molecular tools for transcriptional fine tuning of target genes. Strong overexpression of FBP in human hepatocellular carcinoma (HCC) supports tumor growth and correlates with poor patient prognosis. However, the role of the transcriptional repressor FIR in hepatocarcinogenesis remains poorly delineated. We show that overexpression of FIR correlates with tumor dedifferentiation and tumor cell proliferation in about 60% of primary HCCs. Elevated FIR levels are associated with genomic gains of the FIR gene locus at chromosome 8q24.3 in human HCC specimens. In vitro, nuclear enrichment of FIR supports HCC cell proliferation and migration. Expression profiling of HCC cells after small interfering RNA (siRNA)-mediated silencing of FIR identified the transcription factor DP-1 (TFDP1) as a transcriptional target of FIR. Surprisingly, FIR stimulates the expression of FBP in a TFDP1/E2F1-dependent manner. FIR splice variants lacking or containing exon 2 and/or exon 5 are expressed in the majority of HCCs but not in normal hepatocytes. Specific inhibition of FIR isoforms with and without exon 2 revealed that both groups of FIR splice variants facilitate tumor-supporting effects. This finding was confirmed in xenograft transplantation experiments with lentiviral-infected short hairpin RNA (shRNA) targeting all FIR variants as well as FIR with and without exon 2.
CONCLUSION: High-level nuclear FIR does not facilitate repressor properties but supports tumor growth in HCC cells. Thus, the pharmacological inhibition of FIR might represent a promising therapeutic strategy for HCC patients with elevated FIR expression.

Matsushita K, Shimada H, Ueda Y, et al.
Non-transmissible Sendai virus vector encoding c-myc suppressor FBP-interacting repressor for cancer therapy.
World J Gastroenterol. 2014; 20(15):4316-28 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
AIM: To investigate a novel therapeutic strategy to target and suppress c-myc in human cancers using far up stream element (FUSE)-binding protein-interacting repressor (FIR).
METHODS: Endogenous c-Myc suppression and apoptosis induction by a transient FIR-expressing vector was examined in vivo via a HA-tagged FIR (HA-FIR) expression vector. A fusion gene-deficient, non-transmissible, Sendai virus (SeV) vector encoding FIR cDNA, SeV/dF/FIR, was prepared. SeV/dF/FIR was examined for its gene transduction efficiency, viral dose dependency of antitumor effect and apoptosis induction in HeLa (cervical squamous cell carcinoma) cells and SW480 (colon adenocarcinoma) cells. Antitumor efficacy in a mouse xenograft model was also examined. The molecular mechanism of the anti-tumor effect and c-Myc suppression by SeV/dF/FIR was examined using Spliceostatin A (SSA), a SAP155 inhibitor, or SAP155 siRNA which induce c-Myc by increasing FIR∆exon2 in HeLa cells.
RESULTS: FIR was found to repress c-myc transcription and in turn the overexpression of FIR drove apoptosis through c-myc suppression. Thus, FIR expressing vectors are potentially applicable for cancer therapy. FIR is alternatively spliced by SAP155 in cancer cells lacking the transcriptional repression domain within exon 2 (FIR∆exon2), counteracting FIR for c-Myc protein expression. Furthermore, FIR forms a complex with SAP155 and inhibits mutual well-established functions. Thus, both the valuable effects and side effects of exogenous FIR stimuli should be tested for future clinical application. SeV/dF/FIR, a cytoplasmic RNA virus, was successfully prepared and showed highly efficient gene transduction in in vivo experiments. Furthermore, in nude mouse tumor xenograft models, SeV/dF/FIR displayed high antitumor efficiency against human cancer cells. SeV/dF/FIR suppressed SSA-activated c-Myc. SAP155 siRNA, potentially produces FIR∆exon2, and led to c-Myc overexpression with phosphorylation at Ser62. HA-FIR suppressed endogenous c-Myc expression and induced apoptosis in HeLa and SW480 cells. A c-myc transcriptional suppressor FIR expressing SeV/dF/FIR showed high gene transduction efficiency with significant antitumor effects and apoptosis induction in HeLa and SW480 cells.
CONCLUSION: SeV/dF/FIR showed strong tumor growth suppression with no significant side effects in an animal xenograft model, thus SeV/dF/FIR is potentially applicable for future clinical cancer treatment.

Appin CL, Brat DJ
Molecular genetics of gliomas.
Cancer J. 2014 Jan-Feb; 20(1):66-72 [PubMed] Related Publications
Diffusely infiltrating gliomas are the most common primary brain tumors and include astrocytomas, oligodendrogliomas, and oligoastrocytomas of grades II and III and glioblastoma (GBM), grade IV. Histologic classification is increasingly aided by molecular genetic studies, which assist in the diagnosis and provide prognostic and predictive value. Mutations in IDH1 are frequent in grades II and III astrocytomas, oligodendrogliomas, and oligoastrocytomas, as well as secondary GBMs. IDH1-mutated diffuse gliomas are distinct from their IDH1 wild-type counterparts based on clinical features, growth rates, and concurrent genomic alterations. Grades II and III astrocytomas, as well as secondary GBMs are characterized by IDH1, TP53, and ATRX mutations, whereas oligodendrogliomas most frequently harbor codeletion of 1p/19q and mutations in CIC, FUBP1, and the TERT promoter. Primary GBMs frequently show molecular alterations in EGFR, PDGFRA, PTEN, TP53, NF1, and CDKN2A/B, as well as TERT promoter mutations, but not IDH mutations. Pediatric GBMs have a distinctive molecular pathogenesis, as H3F3A and DAXX mutations are frequent, and their gene expression profile is different than adult GBMs. Other lower-grade gliomas of childhood, such as pilocytic astrocytoma and pleomorphic xanthoastrocytoma, are characterized by BRAF mutations or activating gene rearrangements involving BRAF.

Ding Z, Liu X, Liu Y, et al.
Expression of far upstream element (FUSE) binding protein 1 in human glioma is correlated with c-Myc and cell proliferation.
Mol Carcinog. 2015; 54(5):405-15 [PubMed] Related Publications
Glioma is one of the most common type of primary intracranial tumor. Although great advances have been achieved in treatment of glioma, the underlying molecular mechanisms remain largely unknown. Previous studies demonstrated that FBP1 is a transcriptional regulator of c-Myc and acts as an important prognostic indicator in many cancers. Our study aimed to assess the expression and function of FBP1 in human glioma. Immunohistochemical and Western blot analysis were performed in human glioma and normal brain tissues. High FBP1 expression (located in cell nuclei) was observed in 70 samples and its level was correlated with the grade of malignancy. A strongly positive correlation was observed between FBP1 and c-Myc (P = 0.005) and Ki-67 expression (P = 0.009). In a multivariate analysis, high FBP1 and c-Myc expressions were showed to be associated with poor prognosis in glioma. While in vitro, following serum stimulation of starved U87MG cells, the expression of FBP1 was upregulated, as well as c-Myc and PCNA. Moreover, knockdown of FBP1 by siRNA transfection diminished the expression of c-Myc and arrested cell growth at G1 phase. Collectively, our results shows that the expression of FBP1 is in close correlation with c-Myc level and cell proliferation in glioma and provides a potential strategy to develop FBP1 inhibitors as novel anti-tumor agents.

Lv L, Xu YP, Zhao D, et al.
Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear localization.
Mol Cell. 2013; 52(3):340-52 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Alternative splicing of the PKM2 gene produces two isoforms, M1 and M2, which are preferentially expressed in adult and embryonic tissues, respectively. The M2 isoform is reexpressed in human cancer and has nonmetabolic functions in the nucleus as a protein kinase. Here, we report that PKM2 is acetylated by p300 acetyltransferase at K433, which is unique to PKM2 and directly contacts its allosteric activator, fructose 1,6-bisphosphate (FBP). Acetylation prevents PKM2 activation by interfering with FBP binding and promotes the nuclear accumulation and protein kinase activity of PKM2. Acetylation-mimetic PKM2(K433) mutant promotes cell proliferation and tumorigenesis. K433 acetylation is decreased by serum starvation and cell-cell contact, increased by cell cycle stimulation, epidermal growth factor (EGF), and oncoprotein E7, and enriched in breast cancers. Hence, K433 acetylation links cell proliferation and transformation to the switch of PKM2 from a cytoplasmic metabolite kinase to a nuclear protein kinase.

Baumgarten P, Harter PN, Tönjes M, et al.
Loss of FUBP1 expression in gliomas predicts FUBP1 mutation and is associated with oligodendroglial differentiation, IDH1 mutation and 1p/19q loss of heterozygosity.
Neuropathol Appl Neurobiol. 2014; 40(2):205-16 [PubMed] Related Publications
AIMS: The Far Upstream Element [FUSE] Binding Protein 1 (FUBP1) regulates target genes, such as the cell cycle regulators MYC and p21. FUBP1 is up-regulated in many tumours and acts as an oncoprotein by stimulating proliferation and inhibiting apoptosis. Recently, FUBP1 mutations were identified in approximately 15% of oligodendrogliomas. To date, all reported FUBP1 mutations have been predicted to inactivate FUBP1, which suggests that in contrast to most other tumours FUBP1 may act as a tumour suppressor in oligodendrogliomas.
METHODS: As no data are currently available concerning FUBP1 protein levels in gliomas, we examined the FUBP1 expression profiles of human glial tumours by immunohistochemistry and immunofluorescence. We analysed FUBP1 expression related to morphological differentiation, IDH1 and FUBP1 mutation status, 1p/19q loss of heterozygosity (LOH) as well as proliferation rate.
RESULTS: Our findings demonstrate that FUBP1 expression levels are increased in all glioma subtypes as compared with normal central nervous system (CNS) control tissue and are associated with increased proliferation. In contrast, FUBP1 immunonegativity predicted FUBP1 mutation with a sensitivity of 100% and a specificity of 90% in our cohort and was associated with oligodendroglial differentiation, IDH1 mutation and 1p/19q loss of heterozygosity (LOH). Using this approach, we detected a to-date undescribed FUBP1 mutation in an oligodendroglioma.
CONCLUSION: In summary, our data indicate an association between of FUBP1 expression and proliferation in gliomas. Furthermore, our findings present FUBP1 immunohistochemical analysis as a helpful additional tool for neuropathological glioma diagnostics predicting FUBP1 mutation.

Eisenreich S, Abou-El-Ardat K, Szafranski K, et al.
Novel CIC point mutations and an exon-spanning, homozygous deletion identified in oligodendroglial tumors by a comprehensive genomic approach including transcriptome sequencing.
PLoS One. 2013; 8(9):e76623 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Oligodendroglial tumors form a distinct subgroup of gliomas, characterized by a better response to treatment and prolonged overall survival. Most oligodendrogliomas and also some oligoastrocytomas are characterized by a unique and typical unbalanced translocation, der(1,19), resulting in a 1p/19q co-deletion. Candidate tumor suppressor genes targeted by these losses, CIC on 19q13.2 and FUBP1 on 1p31.1, were only recently discovered. We analyzed 17 oligodendrogliomas and oligoastrocytomas by applying a comprehensive approach consisting of RNA expression analysis, DNA sequencing of CIC, FUBP1, IDH1/2, and array CGH. We confirmed three different genetic subtypes in our samples: i) the "oligodendroglial" subtype with 1p/19q co-deletion in twelve out of 17 tumors; ii) the "astrocytic" subtype in three tumors; iii) the "other" subtype in two tumors. All twelve tumors with the 1p/19q co-deletion carried the most common IDH1 R132H mutation. In seven of these tumors, we found protein-disrupting point mutations in the remaining allele of CIC, four of which are novel. One of these tumors also had a deleterious mutation in FUBP1. Only by integrating RNA expression and array CGH data, were we able to discover an exon-spanning homozygous microdeletion within the remaining allele of CIC in an additional tumor with 1p/19q co-deletion. Therefore we propose that the mutation rate might be underestimated when looking at sequence variants alone. In conclusion, the high frequency and the spectrum of CIC mutations in our 1p/19q-codeleted tumor cohort support the hypothesis that CIC acts as a tumor suppressor in these tumors, whereas FUBP1 might play only a minor role.

Chan AK, Pang JC, Chung NY, et al.
Loss of CIC and FUBP1 expressions are potential markers of shorter time to recurrence in oligodendroglial tumors.
Mod Pathol. 2014; 27(3):332-42 [PubMed] Related Publications
Combined deletion of chromosomes 1p and 19q is a prognostic marker in oligodendroglial tumors. Recent studies in oligodendroglial tumors have unveiled recurrent mutations of CIC (homolog of Drosophila capicua) and FUBP1 (far upstream element binding protein 1) that are located on 19q13 and 1p31, respectively. However, the impact of CIC and FUBP1 mutations on their protein expressions has not been examined. The aims of this study were to correlate the expression patterns of CIC and FUBP1 with their mutation profiles and to evaluate the clinical relevance of these molecular markers in 55 oligodendroglial tumors diagnosed in 47 adult patients. Using direct sequencing, somatic mutations of CIC and FUBP1 were identified in 47% (22/47) and 16% (7/45) of oligodendroglial tumors, respectively. Immunohistochemical analysis revealed loss of CIC or FUBP1 protein expression in 36% (20/55) and 16% (9/55) of oligodendroglial tumors examined. Somatic mutation was significantly associated with absent protein expression for both genes (CIC, P=0.01; FUBP1, P=0.00001). Four tumors with undetectable CIC mutations exhibited absent CIC expression, suggesting that CIC inactivation could be mediated by mechanisms other than mutations and genomic loss. Univariate survival analysis revealed that 1p/19q codeletion was significantly associated with overall survival (P=0.05). Loss of CIC expression was significantly correlated with shorter progression-free survival (P=0.03), whereas CIC alteration (mutation or null expression) with worse overall survival (P=0.05). Absent FUBP1 expression was linked with unfavorable progression-free survival (P=0.02) and overall survival (P=0.01). In 16 tumors with 1p/19q codeletion, CIC mutation was associated with unfavorable survival (P=0.01). There was a correlation between lack of CIC or FUBP1 expression and poor progression-free survival (P=0.004; P=0.0003). No molecular markers showed association with survival in oligodendroglial tumors lacking 1p/19q codeletion. We conclude that absent CIC and FUBP1 expressions are potential markers of shorter time to recurrence and CIC mutation a potential marker of worse prognosis, especially in tumors carrying 1p/19q codeletion.

Wang D, Moothart DR, Lowy DR, Qian X
The expression of glyceraldehyde-3-phosphate dehydrogenase associated cell cycle (GACC) genes correlates with cancer stage and poor survival in patients with solid tumors.
PLoS One. 2013; 8(4):e61262 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is often used as a stable housekeeping marker for constant gene expression. However, the transcriptional levels of GAPDH may be highly up-regulated in some cancers, including non-small cell lung cancers (NSCLC). Using a publically available microarray database, we identified a group of genes whose expression levels in some cancers are highly correlated with GAPDH up-regulation. The majority of the identified genes are cell cycle-dependent (GAPDH Associated Cell Cycle, or GACC). The up-regulation pattern of GAPDH positively associated genes in NSCLC is similar to that observed in cultured fibroblasts grown under conditions that induce anti-senescence. Data analysis demonstrated that up-regulated GAPDH levels are correlated with aberrant gene expression related to both glycolysis and gluconeogenesis pathways. Down-regulation of fructose-1,6-bisphosphatase (FBP1) in gluconeogenesis in conjunction with up-regulation of most glycolytic genes is closely related to high expression of GAPDH in the tumors. The data presented demonstrate that up-regulation of GAPDH positively associated genes is proportional to the malignant stage of various tumors and is associated with an unfavourable prognosis. Thus, this work suggests that GACC genes represent a potential new signature for cancer stage identification and disease prognosis.

Klink B, Miletic H, Stieber D, et al.
A novel, diffusely infiltrative xenograft model of human anaplastic oligodendroglioma with mutations in FUBP1, CIC, and IDH1.
PLoS One. 2013; 8(3):e59773 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Oligodendroglioma poses a biological conundrum for malignant adult human gliomas: it is a tumor type that is universally incurable for patients, and yet, only a few of the human tumors have been established as cell populations in vitro or as intracranial xenografts in vivo. Their survival, thus, may emerge only within a specific environmental context. To determine the fate of human oligodendroglioma in an experimental model, we studied the development of an anaplastic tumor after intracranial implantation into enhanced green fluorescent protein (eGFP) positive NOD/SCID mice. Remarkably after nearly nine months, the tumor not only engrafted, but it also retained classic histological and genetic features of human oligodendroglioma, in particular cells with a clear cytoplasm, showing an infiltrative growth pattern, and harboring mutations of IDH1 (R132H) and of the tumor suppressor genes, FUBP1 and CIC. The xenografts were highly invasive, exhibiting a distinct migration and growth pattern around neurons, especially in the hippocampus, and following white matter tracts of the corpus callosum with tumor cells accumulating around established vasculature. Although tumors exhibited a high growth fraction in vivo, neither cells from the original patient tumor nor the xenograft exhibited significant growth in vitro over a six-month period. This glioma xenograft is the first to display a pure oligodendroglioma histology and expression of R132H. The unexpected property, that the cells fail to grow in vitro even after passage through the mouse, allows us to uniquely investigate the relationship of this oligodendroglioma with the in vivo microenvironment.

Sahm F, Lass U, Herold-Mende C, et al.
Analysis of CIC-associated CpG island methylation in oligoastrocytoma.
Neuropathol Appl Neurobiol. 2013; 39(7):831-6 [PubMed] Related Publications
AIMS: Combined deletion of the whole chromosomal arms 1p and 19q is a frequent event in oligodendroglial tumours. Recent identification of recurrent mutations in CIC on 19q and FUBP1 on 1p and their mutational patterns suggest a loss of function of the respective proteins. Surprisingly, oligoastrocytomas harbouring identical genetic characteristics regarding 1p/19q codeletion and frequent IDH1/2 mutations have been shown to carry CIC mutations in a significantly lower number of cases. The present study investigates whether epigenetic modification may result in silencing of CIC.
METHODS: As IDH1/2 mutation-mediated DNA hypermethylation is a prominent feature of these tumours, we analysed a set of CIC wild-type oligoastrocytomas and other diffuse gliomas with regard to 1p/19q status for presence of CIC-associated CpG island methylation by methylation-specific PCR.
RESULTS: Both methylation-specific PCR and subsequent bisulphite-sequencing of selected cases revealed an unmethylated status in all samples.
CONCLUSION: Despite the hypermethylator phenotype in IDH1/2 mutant tumours and recent detection of gene silencing particularly on retained alleles in oligodendroglial tumours, hypermethylation of CIC-associated CpG islands does not provide an alternative mechanism of functional CIC protein abrogation.

Jones PS, Dunn GP, Barker FG, et al.
Molecular genetics of low-grade gliomas: genomic alterations guiding diagnosis and therapeutic intervention. 11th annual Frye-Halloran Brain Tumor Symposium.
Neurosurg Focus. 2013; 34(2):E9 [PubMed] Related Publications
OBJECT: The authors' goal was to review the current understanding of the underlying molecular and genetic mechanisms involved in low-grade glioma development and how these mechanisms can be targets for detection and treatment of the disease and its recurrence.
METHODS: On October 4, 2012, the authors convened a meeting of researchers and clinicians across a variety of pertinent medical specialties to review the state of current knowledge on molecular genetic mechanisms of low-grade gliomas and to identify areas for further research and drug development.
RESULTS: The meeting consisted of 3 scientific sessions ranging from neuropathology of IDH1 mutations; CIC, ATRX, and FUBP1 mutations in oligodendrogliomas and astrocytomas; and IDH1 mutations as therapeutic targets. Sessions consisted of a total of 10 talks by international leaders in low-grade glioma research, mutant IDH1 biology and its application in glioma research, and treatment.
CONCLUSIONS: The recent discovery of recurrent gene mutations in low-grade glioma has increased the understanding of the molecular mechanisms involved in a host of biological activities related to low-grade gliomas. Understanding the role these genetic alterations play in brain cancer initiation and progression will help lead to the development of novel treatment modalities than can be personalized to each patient, thereby helping transform this now often-fatal malignancy into a chronic or even curable disease.

Kajiwara T, Matsushita K, Itoga S, et al.
SAP155-mediated c-myc suppressor far-upstream element-binding protein-interacting repressor splicing variants are activated in colon cancer tissues.
Cancer Sci. 2013; 104(2):149-56 [PubMed] Related Publications
The c-myc transcriptional suppressor, far-upstream element (FUSE)-binding protein (FBP)-interacting repressor (FIR), is alternatively spliced in colorectal cancer tissue (Matsushita et al., Cancer Res 2006). Recently, the knockdown of SAP155 pre-mRNA-splicing factor, a subunit of SF3b, was reported to disturb FIR pre-mRNA splicing and yield FIRΔexon2, an exon 2-spliced variant of FIR, which lacks c-myc repression activity. In the present study, novel splicing variants of FIR, Δ3 and Δ4, were also generated by SAP155 siRNA, and these variants were found to be activated in human colorectal cancer tissue. Furthermore, the expression levels of FIR variant mRNA were examined in the peripheral blood of colorectal cancer patients and healthy volunteers to assess its potency for tumor detection. As expected, circulating FIR variant mRNA in the peripheral blood of cancer patients were significantly overexpressed compared to that in healthy volunteers. In particular, the area under the receiving operating characteristic curve of FIR, FIRΔexon2 or FIRΔexon2/FIR, was greater than those of conventional carcinoembryonic antigen or carbohydrate antigen 19-9. In addition, FIRΔexon2 or FIR mRNA expression in the peripheral blood was significantly reduced after operative removal of colorectal tumors. Thus, circulating FIR and FIRΔexon2 mRNA are potential novel screening markers for colorectal cancer testing with conventional carcinoembryonic antigen and or carbohydrate antigen 19-9. Taken together, our results indicate that overexpression of FIR and its splicing variants in colorectal cancer directs feed-forward or addicted circuit c-myc transcriptional activation. Clinical implications for colorectal cancers of novel FIR splicing variants are also discussed in the present paper.

Idbaih A, Ducray F, Dehais C, et al.
SNP array analysis reveals novel genomic abnormalities including copy neutral loss of heterozygosity in anaplastic oligodendrogliomas.
PLoS One. 2012; 7(10):e45950 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Anaplastic oligodendrogliomas (AOD) are rare glial tumors in adults with relative homogeneous clinical, radiological and histological features at the time of diagnosis but dramatically various clinical courses. Studies have identified several molecular abnormalities with clinical or biological relevance to AOD (e.g. t(1;19)(q10;p10), IDH1, IDH2, CIC and FUBP1 mutations).To better characterize the clinical and biological behavior of this tumor type, the creation of a national multicentric network, named "Prise en charge des OLigodendrogliomes Anaplasiques (POLA)," has been supported by the Institut National du Cancer (InCA). Newly diagnosed and centrally validated AOD patients and their related biological material (tumor and blood samples) were prospectively included in the POLA clinical database and tissue bank, respectively.At the molecular level, we have conducted a high-resolution single nucleotide polymorphism array analysis, which included 83 patients. Despite a careful central pathological review, AOD have been found to exhibit heterogeneous genomic features. A total of 82% of the tumors exhibited a 1p/19q-co-deletion, while 18% harbor a distinct chromosome pattern. Novel focal abnormalities, including homozygously deleted, amplified and disrupted regions, have been identified. Recurring copy neutral losses of heterozygosity (CNLOH) inducing the modulation of gene expression have also been discovered. CNLOH in the CDKN2A locus was associated with protein silencing in 1/3 of the cases. In addition, FUBP1 homozygous deletion was detected in one case suggesting a putative tumor suppressor role of FUBP1 in AOD.Our study showed that the genomic and pathological analyses of AOD are synergistic in detecting relevant clinical and biological subgroups of AOD.

Alentorn A, Sanson M, Idbaih A
Oligodendrogliomas: new insights from the genetics and perspectives.
Curr Opin Oncol. 2012; 24(6):687-93 [PubMed] Related Publications
PURPOSE OF REVIEW: Since the discovery, in 1994, of recurrent codeletion of chromosome regions 1p36/19q13 in oligodendrogliomas, genetics has accomplished significant advances improving our knowledge in biology of this tumor type and our clinical management of oligodendroglioma patients. Indeed, 1p36/19q13 has been shown successively to predict increased chemosensitivity and better prognosis, to be associated with frontal location in brain and classic oligodendroglioma morphology, to be mutually exclusive with high-level gene amplification, to be actually whole chromosome arms 1p/19q codeletion, to mediate a t(1;19)(q10;p10) and to be associated with IDH mutations. More recently, pivotal studies, using high-throughput approaches, have provided significant novel insights in the molecular oncogenesis of oligodendrogliomas.
RECENT FINDINGS: Capicua homolog (Drosophila) (CIC) and Far Upstream element Binding Protein 1 (FUBP1) have been shown to be frequently mutated in 70 and 40% of 1p/19q codeleted oligodendrogliomas, respectively. The biological and clinical significance of these mutations remains unsettled. Additional recent studies have also demonstrated that 1p/19q codeleted oligodendrogliomas exhibit a proneural transcriptomic profile including overexpression of internexin alpha, a neuronal intermediate filament. Finally, 1p/19q codeleted and IDH-mutated tumors have been shown to be hypermethylated, suggesting a strong link between these both molecular alterations detected in the subgroup of oligodendrogliomas with better prognosis.
SUMMARY: Next-generation molecular biology technologies have recently identified recurrent CIC and FUBP1 point mutations in 1p/19q codeleted and IDH-mutated oligodendrogliomas. Their clinical and biological values are under investigation.

Jiao Y, Killela PJ, Reitman ZJ, et al.
Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas.
Oncotarget. 2012; 3(7):709-22 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Mutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas ( more than 10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.

Stordal B, Hamon M, McEneaney V, et al.
Resistance to paclitaxel in a cisplatin-resistant ovarian cancer cell line is mediated by P-glycoprotein.
PLoS One. 2012; 7(7):e40717 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy.

Sahm F, Koelsche C, Meyer J, et al.
CIC and FUBP1 mutations in oligodendrogliomas, oligoastrocytomas and astrocytomas.
Acta Neuropathol. 2012; 123(6):853-60 [PubMed] Related Publications
CIC and FUBP1 mutations have recently been detected in oligodendrogliomas but not in oligoastrocytomas. However, allelic losses in the regions on chromosomal arms 19q and 1p harboring CIC and FUBP1 are a common feature of both, oligodendrogliomas and oligoastrocytomas. To resolve this discrepancy, we analyzed CIC and FUBP1 mutations in a set of primary brain tumors including 18 oligodendrogliomas and 42 oligoastrocytomas. In addition, we analyzed 10 astrocytomas and 16 glioblastomas with allelic losses on 19q as well as a set of 12 medulloblastomas for CIC mutations. CIC mutations were found in 15/18 oligodendrogliomas, 14/42 oligoastrocytomas and 3/10 preselected astrocytomas. With the exception of a single case, all CIC mutations occurred in tumors with combined 1p/19q losses. In contrast to oligodendrogliomas where CIC mutations were always detected along with 1p/19q co-deletion, CIC mutations were only found in 52 % of the 1p/19q co-deleted oligoastrocytomas. FUBP1 mutations were detected in 7/61 tumors, all presenting with CIC mutations. FUBP1 mutations appear to cluster in the DNA binding domain spanning exons 5-14. CIC and FUBP1 mutations exclusively occurred in presence of either IDH1 or IDH2 mutations. Our data confirm CIC and FUBP1 mutations in oligodendrogliomas and demonstrate the presence of these mutations in oligoastrocytomas.

Zheng Y, Miskimins WK
Far upstream element binding protein 1 activates translation of p27Kip1 mRNA through its internal ribosomal entry site.
Int J Biochem Cell Biol. 2011; 43(11):1641-8 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
The cyclin dependent kinase inhibitor p27 plays an important role in controlling the eukaryotic cell cycle by regulating progression through G1 and entry into S phase. It is often elevated during differentiation and under conditions of cellular stress. In contrast, it is commonly downregulated in cancer cells and its levels are generally inversely correlated with favorable prognosis. The cellular levels of p27 are regulated, in part, by translational control mechanisms. The 5'-untranslated region (5'-UTR) of the p27 mRNA harbors an internal ribosome entry site (IRES) which may facilitate synthesis of p27 in certain conditions. In this study, Far Upstream Element (FUSE) Binding Protein 1 (FBP1) was shown to directly bind to the human p27 5'-UTR and to promote IRES activity. An eight-nucleotide element downstream of a U-rich region within the 5'-UTR was important for FBP1 binding and p27 IRES activity. Overexpression of FBP1 enhanced endogenous p27 levels and stimulated translation initiation. In contrast, repression of FBP1 by siRNA transfection downregulated endogenous p27 protein levels. Using rabbit reticulocyte lysates, FBP1 stimulated p27 mRNA translation in vitro. The central domain of FBP1, containing four K homology motifs, was required for p27 5'-UTR RNA binding and the N terminal domain was important for translational activation. These findings indicate that FBP1 is a novel activator of p27 translation upon binding to the 5'-UTR.

Bettegowda C, Agrawal N, Jiao Y, et al.
Mutations in CIC and FUBP1 contribute to human oligodendroglioma.
Science. 2011; 333(6048):1453-5 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Oligodendrogliomas are the second most common malignant brain tumor in adults and exhibit characteristic losses of chromosomes 1p and 19q. To identify the molecular genetic basis for this alteration, we performed exomic sequencing of seven tumors. Among other changes, we found that the CIC gene (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in six cases and that the FUBP1 gene [encoding far-upstream element (FUSE) binding protein] on chromosome 1p was somatically mutated in two tumors. Examination of 27 additional oligodendrogliomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. These results suggest a critical role for these genes in the biology and pathology of oligodendrocytes.

Atanassov BS, Dent SY
USP22 regulates cell proliferation by deubiquitinating the transcriptional regulator FBP1.
EMBO Rep. 2011; 12(9):924-30 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Ubiquitin-specific protease 22 (USP22) edits the histone code by deubiquitinating H2A and H2B as part of the mammalian SAGA (Spt-Ada-Gcn5) complex, and is required for transcriptional regulation and normal cell-cycle progression. Here, we show that USP22 affects the expression of p21 by altering far upstream element (FUSE)-binding protein 1 (FBP1) ubiquitination, as ablation of USP22 leads to increased FBP1 ubiquitination and decreased FBP1 protein occupancy at the p21 gene. Surprisingly, increased polyubiquitination of FBP1 does not alter its protein stability, but instead modulates the stable recruitment of FBP1 to target loci. Our results indicate a mechanism by which USP22 regulates cell proliferation and tumorigenesis.

Brauckhoff A, Malz M, Tschaharganeh D, et al.
Nuclear expression of the ubiquitin ligase seven in absentia homolog (SIAH)-1 induces proliferation and migration of liver cancer cells.
J Hepatol. 2011; 55(5):1049-57 [PubMed] Related Publications
BACKGROUND & AIMS: Differential expression of tumor-relevant proteins based on aberrant proteasomal degradation may contribute to human (hepato)carcinogenesis. Recently, we identified the E3 ubiquitin ligase seven in absentia homolog (SIAH)-1 as frequently dysregulated in human hepatocellular carcinoma (HCC). We therefore systematically analyzed the expression, functional relevance, as well as possible downstream effectors of SIAH-1 in human liver carcinogenesis.
METHODS: SIAH-1 expression was analyzed at the transcript and protein levels in human hepatocarcinogenesis and in HCC cells. Proliferation, apoptosis, and migration of different HCC cell lines were examined after siRNA-mediated inhibition of SIAH-1. In order to identify downstream effectors that mediate SIAH-1 effects, correlative analyses of protein expression profiles were performed.
RESULTS: In HCC tissues both reduction of cytoplasmic SIAH-1 and especially its nuclear accumulation positively correlated with HCC progression. RNA interference revealed that nuclear expression of SIAH-1 predominantly supported HCC cell proliferation and migration while only moderately affecting anti-apoptosis. In de-differentiated human HCCs, nuclear SIAH-1 accumulation significantly correlated with the expression of the transcription factor far-upstream element (FUSE)-binding protein (FBP)-3. In vitro, SIAH-1 positively and indirectly regulated FBP-3 which itself primarily supported HCC cell proliferation. Indeed, high level expression of FBP-3 in human HCCs significantly correlated with reduced overall survival of patients.
CONCLUSIONS: Nuclear accumulation of the E3 ubiquitin ligase SIAH-1 supports different pro-tumorigenic cellular processes associated with tumor growth and tumor cell dissemination in human hepatocarcinogenesis. It promotes HCC cell proliferation by at least partly employing the transcription factor FBP-3. Therefore, interference with SIAH-1 activity represents a promising approach to suppress HCC growth.

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