Gene Summary

Gene:YEATS4; YEATS domain containing 4
Aliases: YAF9, GAS41, NUBI-1, 4930573H17Rik, B230215M10Rik
Summary:The protein encoded by this gene is found in the nucleoli. It has high sequence homology to human MLLT1, and yeast and human MLLT3 proteins. Both MLLT1 and MLLT3 proteins belong to a class of transcription factors, indicating that the encoded protein might also represent a transcription factor. This protein is thought to be required for RNA transcription. This gene has been shown to be amplified in tumors. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:YEATS domain-containing protein 4
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: YEATS4 (cancer-related)

Hsu CC, Shi J, Yuan C, et al.
Recognition of histone acetylation by the GAS41 YEATS domain promotes H2A.Z deposition in non-small cell lung cancer.
Genes Dev. 2018; 32(1):58-69 [PubMed] Free Access to Full Article Related Publications
Histone acetylation is associated with active transcription in eukaryotic cells. It helps to open up the chromatin by neutralizing the positive charge of histone lysine residues and providing binding platforms for "reader" proteins. The bromodomain (BRD) has long been thought to be the sole protein module that recognizes acetylated histones. Recently, we identified the YEATS domain of AF9 (ALL1 fused gene from chromosome 9) as a novel acetyl-lysine-binding module and showed that the ENL (eleven-nineteen leukemia) YEATS domain is an essential acetyl-histone reader in acute myeloid leukemias. The human genome encodes four YEATS domain proteins, including GAS41, a component of chromatin remodelers responsible for H2A.Z deposition onto chromatin; however, the importance of the GAS41 YEATS domain in human cancer remains largely unknown. Here we report that

Jixiang C, Shengchun D, Jianguo Q, et al.
YEATS4 promotes the tumorigenesis of pancreatic cancer by activating beta-catenin/TCF signaling.
Oncotarget. 2017; 8(15):25200-25210 [PubMed] Free Access to Full Article Related Publications
Beta-catenin/TCF signaling has been reported to promote the growth and metastasis of pancreatic cancer cells. However, the regulation for the beta-catenin/TCF transcriptional complex remains largely unknown. Here, we have found that YEATS4 is a positive regulator for Beta-catenin/TCF signaling. The expression of YEATS4 was elevated in clinical pancreatic cancer samples and pancreatic cancer mouse model. Up-regulation of YEATS4 promoted the growth, migration and invasion of pancreatic cancer cells, while knocking down the expression of YEATS4 inhibited the growth, migration, invasion and metastasis of pancreatic cancer cells. Moreover, the mechanism study revealed that YEATS4 interacted with beta-catenin and activated beta-catenin/TCF signaling. Furthermore, knocking down the expression of YEATS4 impaired the malignant transformation of normal pancreatic cells (HPDE6C7) by the oncogenic Ras. Taken together, our study demonstrated the oncogenic roles of YEATS4 in the progression of pancreatic cancer by activating beta-catenin/TCF signaling and suggested that YEATS4 might be a promising therapeutic target for pancreatic cancer.

Zhao D, Li Y, Xiong X, et al.
YEATS Domain-A Histone Acylation Reader in Health and Disease.
J Mol Biol. 2017; 429(13):1994-2002 [PubMed] Related Publications
Histone post-translational modifications (PTMs) carry an epigenetic layer of message to regulate diverse cellular processes at the chromatin level. Many of these PTMs are selectively recognized by dedicated effector proteins for normal cell growth and development, while dysregulation of these recognition events is often implicated in human diseases, notably cancer. Thus, it is fundamentally important to elucidate the regulatory mechanism(s) underlying the readout of PTMs on histones. The Yaf9, ENL, AF9, Taf14, Sas5 (YEATS) domain is an emerging reader module that selectively recognizes histone lysine acylation with a preference for crotonylation over acetylation. In the review, we discuss the recognition of histone acylations by the YEATS domain and the biological significance of this readout from multiple perspectives.

Fu Q, Cheng J, Zhang J, et al.
Downregulation of YEATS4 by miR-218 sensitizes colorectal cancer cells to L-OHP-induced cell apoptosis by inhibiting cytoprotective autophagy.
Oncol Rep. 2016; 36(6):3682-3690 [PubMed] Related Publications
Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Deregulation of microRNAs (miRNAs) has been reported to participate in CRC progression. In the present study, we observed downregulation of miR-218 and upregulation of YEATS domain containing 4 (YEATS4) in CRC tissues and in multidrug-resistant HCT-116/L-OHP cells compared with these levels in normal tissues and parental HCT-116 cells, respectively. The results indicated that miR-218 overexpression significantly decreased the IC50 value of oxaliplatin (L-OHP) in the HCT-116/L-OHP cells, and suppression of miR-218 significantly enhanced the IC50 of L-OHP in the HCT-116 cells. Flow cytometric analysis showed that miR-218 overexpression alone promoted cell apoptosis in the HCT-116/L-OHP cells, which was further enhanced in response to L-OHP, and miR-218 inhibition decreased cell apoptosis in the HCT-116 cells following treatment with L-OHP. Western blot analysis indicated that, compared with the small increase observed in HCT-116 cells, the relative LC3 II level in HCT-116/L-OHP cells after lysosome inhibition via chloroquine (CQ) was markedly upregulated following L-OHP treatment, suggesting induction of autophagy. Exposure of HCT-116/L-OHP cells to L-OHP after control mimic transfection increased autophagic flux, as reflected by increased LC3 II levels, while miR-218 overexpression partly reversed L-OHP-mediated LC3 II accumulation. Additionally, both miR-218 overexpression and CQ treatment promoted L-OHP-induced HCT-116/L-OHP cell apoptosis. Molecularly, our results confirmed that miR-218 directly targets the YEATS4 gene and inhibits YEATS4 expression. Furthermore, YEATS4 overexpression without the 3'-untranslated region (3'-UTR) restored miR-218-inhibited YEATS4 and LC3 II expression, and abolished miR-218-stimulated cell viability loss and cell apoptosis increase in response to L-OHP. In conclusion, miR-218 sensitized HCT-116/L-OHP cells to L-OHP-induced cell apoptosis via inhibition of cytoprotective autophagy by targeting YEATS4 expression.

Pal D, Mukhopadhyay D, Ramaiah MJ, et al.
Regulation of Cell Proliferation and Migration by miR-203 via GAS41/miR-10b Axis in Human Glioblastoma Cells.
PLoS One. 2016; 11(7):e0159092 [PubMed] Free Access to Full Article Related Publications
Glioma amplified sequence 41(GAS41) is a potent transcription factor that play a crucial role in cell proliferation and survival. In glioblastoma, the expression of GAS41 at both transcriptional and post transcriptional level needs to be tightly maintained in response to cellular signals. Micro RNAs (miRNA) are small non coding RNA that act as important regulators for modulating the expression of various target genes. Studies have shown that several miRNAs play role in the post-transcriptional regulation of GAS41. Here we identified GAS41 as a novel target for endogenous miR-203 and demonstrate an inverse correlation of miR-203 expression with GAS41 in glioma cell lines (HNGC2 and U87). Over expression of miR-203 negatively regulates GAS41 expression in U87 and HNGC2 cell lines. Moreover, miR-203 restrained miR-10b action by suppressing GAS41. GAS41 is essential for repressing p53 in tumor suppressor pathway during cell proliferation. Enforced expression of GAS41 produced contradictory effect on miR-203 but was able to enhance p53 tumor suppressor pathway associated protein. It was also found that miR-203 maintains the stability of p53 as knock down of p53 expression using siRNA resulted in down regulation of pri-miR and mature miR-203 expression. Conversely reconstitution of miR-203 expression induced apoptosis and inhibited migratory property of glioma cells. Taken together, we show that miR-203 is a key negative regulator of GAS41 and acts as tumor suppressor microRNA in glioma.

Lee JC, Lu TP, Changou CA, et al.
Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup.
Mod Pathol. 2016; 29(9):1070-82 [PubMed] Related Publications
Müllerian adenosarcomas are malignant gynecologic neoplasms. Advanced staging and sarcomatous overgrowth predict poor prognosis. Because the genomic landscape remains poorly understood, we conducted this study to characterize the genomewide copy number variations in adenosarcomas. Sixteen tumors, including eight with and eight without sarcomatous overgrowth, were subjected to a molecular inversion probe array analysis. Copy number variations, particularly losses, were significantly higher in cases with sarcomatous overgrowth. Frequent gains of chromosomal 12q were noted, often involving cancer-associated genes CDK4 (six cases), MDM2, CPM, YEATS4, DDIT3, GLI1 (five each), HMGA2 and STAT6 (four), without association with sarcomatous overgrowth status. The most frequent losses involved chromosomes 13q (five cases), 9p, 16q and 17q (four cases each) and were almost limited to cases with sarcomatous overgrowth. MDM2 and CDK4 amplification, as well as losses of RB1 (observed in two cases) and CDKN2A/B (one case), was verified by FISH. By immunohistochemistry, all MDM2/CDK4-coamplified cases were confirmed to overexpress both encoded proteins, whereas all four cases with (plus an additional four without) gain of HMGA2 overexpressed the HMGA2 protein. Both cases with RB1 loss were negative for the immunostaining of the encoded protein. Chromothripsis-like copy number profiles involving chromosome 12 or 14 were observed in three fatal cases, all of which harbored sarcomatous overgrowth. With whole chromosome painting and deconvolution fluorescent microscopy, dividing tumor cells in all three cases were shown to have scattered extrachromosomal materials derived from chromosomes involved by chromothripsis, suggesting that this phenomenon may serve as visual evidence for chromothripsis in paraffin tissue. In conclusion, we identified frequent chromosome 12q amplifications, including loci containing potential pharmacological targets. Global chromosomal instability and chromothripsis were more frequent in cases with sarcomatous overgrowth. To our knowledge, this is the first time that evidence of chromothripsis has been demonstrated in paraffin-embedded clinical tissues and in adenosarcomas.

Kim YR, Park MS, Eum KH, et al.
Transcriptome analysis indicates TFEB1 and YEATS4 as regulatory transcription factors for drug resistance of ovarian cancer.
Oncotarget. 2015; 6(31):31030-8 [PubMed] Free Access to Full Article Related Publications
Ovarian cancer is an intractable disease because patients with ovarian cancer frequently develop drug resistance after long-term chemotherapy. Despite the availability of cumulative information on drug-resistant patients, strategies to reverse drug resistance have still not been established. In this study, we analyzed drug resistance-associated transcription factors (TFs) in ovarian cancer. Gene expression profiles of 15 drug-resistant and 11 drug-sensitive patients with ovarian cancer were compared. Our results showed that TFs TFEB1 and YEATS4 regulated the expression of downstream target genes. These 2 TFs have already been implicated in tumorigenesis or metastasis. To our knowledge, this is the first study to evaluate the involvement of these TFs in drug resistance of ovarian cancer. Interestingly, 70% knockdown of each of these TFs with siRNAs resulted in approximately 20%~30% recovery of drug sensitivity. Further, combination treatment of ovarian cancer cells with TFEB1 and YEATS4 siRNAs resulted in 35% reversal of drug resistance. The effect of these TFs on chemoresistance seemed to be associated with intrinsic apoptosis-related pathways, such as p53 activation, and not with the suppression of drug transport. Thus, we suggest a novel approach to reverse chemoresistance of ovarian cancer by suppressing TFEB1 and YEATS4.

Creytens D, Van Gorp J, Speel EJ, Ferdinande L
Characterization of the 12q amplicons in lipomatous soft tissue tumors by multiplex ligation-dependent probe amplification-based copy number analysis.
Anticancer Res. 2015; 35(4):1835-42 [PubMed] Related Publications
BACKGROUND/AIM: Well-differentiated liposarcoma (WDLPS) and de-differentiated liposarcoma (DDLPS) are characterized by amplified sequences derived from the long arm of chromosome 12. The goal of the present study was to identify, besides the well-known candidate genes, novel relevant genes in these large, complex 12q amplicons.
MATERIALS AND METHODS: Using multiplex ligation-dependent probe amplification, genetic alterations in 19 different genes of 12q12-24 were evaluated in 77 lipomatous soft tissue tumors (including lipomas, WDLPS, DDLPS and pleomorphic liposarcomas).
RESULTS: We recorded several amplified genes of 12q13-15, including miR-26a-2, a gene not well studied in liposarcoma, and the well-known and previously described genes murine double minute 2 (MDM2), YEATS domain-containing protein 4 (YEATS4), high-mobility AT-hook 2 (HMGA2), cyclin-dependent kinase 4 (CDK4) and tetraspanin 31 (TSPAN31). Interestingly, the amplification profiles of these six genes were found to be significantly different between WDLPS and DDLPS, more frequently having a high-level status in DDLPS than in WDLPS. In addition, DDLPS were found to have significantly higher mean amplification ratios compared to WDLPS. Moreover, we identified additional genes exclusively amplified in DDLPS in 12q13, 12q21 and 12q24, including glioma-associated oncogene homolog 1 (GLI1), mitogen activated protein kinase kinase kinase 12 (MAP3K12), cyclin-dependent kinase 2 (CDK2), ALX homeobox 1 (ALX1) and T-box 5 (TBX5).
CONCLUSION: Differences in amplification profiles among WDLPS and DDLPS may be related to progression/de-differentiation in liposarcomas and show how in the future amplification profiles could provide an adjunctive tool in characterizing progression to DDLPS. In addition, we identified additional genes exclusively amplified in DDLPS, which may play a role in liposarcomagenesis, particularly in the de-differentiation process.

Pikor LA, Lockwood WW, Thu KL, et al.
YEATS4 is a novel oncogene amplified in non-small cell lung cancer that regulates the p53 pathway.
Cancer Res. 2013; 73(24):7301-12 [PubMed] Free Access to Full Article Related Publications
Genetic analyses of lung cancer have helped found new treatments in this disease. We conducted an integrative analysis of gene expression and copy number in 261 non-small cell lung cancers (NSCLC) relative to matched normal tissues to define novel candidate oncogenes, identifying 12q13-15 and more specifically the YEATS4 gene as amplified and overexpressed in ~20% of the NSCLC cases examined. Overexpression of YEATS4 abrogated senescence in human bronchial epithelial cells. Conversely, RNAi-mediated attenuation of YEATS4 in human lung cancer cells reduced their proliferation and tumor growth, impairing colony formation and inducing cellular senescence. These effects were associated with increased levels of p21WAF1 and p53 and cleavage of PARP, implicating YEATS4 as a negative regulator of the p21-p53 pathway. We also found that YEATS4 expression affected cellular responses to cisplastin, with increased levels associated with resistance and decreased levels with sensitivity. Taken together, our findings reveal YEATS4 as a candidate oncogene amplified in NSCLC, and a novel mechanism contributing to NSCLC pathogenesis.

Ohata H, Miyazaki M, Otomo R, et al.
NuMA is required for the selective induction of p53 target genes.
Mol Cell Biol. 2013; 33(12):2447-57 [PubMed] Free Access to Full Article Related Publications
The p53 tumor suppressor protein is a transcription factor controlling various outcomes, such as growth arrest and apoptosis, through the regulation of different sets of target genes. The nuclear mitotic apparatus protein (NuMA) plays important roles in spindle pole organization during mitosis and in chromatin regulation in the nucleus during interphase. Although NuMA has been shown to colocalize with several nuclear proteins, including high-mobility-group proteins I and Y and GAS41, the role of NuMA during interphase remains unclear. Here we report that NuMA binds to p53 to modulate p53-mediated transcription. Acute and partial ablation of NuMA attenuates the induction of the proarrested p21 gene following DNA damage, subsequently causing impaired cell cycle arrest. Interestingly, NuMA knockdown had little effect on the induction of the p53-dependent proapoptotic PUMA gene. Furthermore, NuMA is required for the recruitment of cyclin-dependent kinase 8 (Cdk8), a component of the Mediator complex and a promoter of p53-mediated p21 gene function. These data demonstrate that NuMA is critical for the target selectivity of p53-mediated transcription.

Pedeutour F, Maire G, Pierron A, et al.
A newly characterized human well-differentiated liposarcoma cell line contains amplifications of the 12q12-21 and 10p11-14 regions.
Virchows Arch. 2012; 461(1):67-78 [PubMed] Related Publications
While surgery is the usual treatment for localized well-differentiated and dedifferentiated liposarcomas (WDLPS/DDLPS), the therapeutic options for patients with advanced disease are limited. The classical antimitotic treatments are most often inefficient. The establishment of genetically characterized cell lines is therefore crucial for providing in vitro models for novel targeted therapies. We have used spectral karyotyping, fluorescence in situ hybridization with whole chromosome painting and locus-specific probes, and array-comparative genomic hybridization to identify the chromosomal and molecular alterations of a novel cell line established from a recurring sclerosing WDLPS. The karyotype was hypertriploid and showed multiple structural anomalies. All cells retained the presence of a giant marker chromosome that had been previously identified in the primary cell cultures. This giant chromosome contained high-level amplification of chromosomal regions 12q13-21 and lacked the alpha-satellite centromeric sequences associated with WDLPS/DDLPS. The 12q amplicon was large, containing 370 amplified genes. The DNA copy number ranged from 3 to 57. The highest levels of amplification were observed at 12q14.3 for GNS, WIF1, and HMGA2. We analyzed the mRNA expression status by real-time reverse transcription polymerase chain reaction for six genes from this amplicon: MDM2, HMGA2, CDK4, TSPAN31, WIF1, and YEATS4. mRNA overexpression was correlated with genomic amplification. A second amplicon originating from 10p11-14 was also present in the giant marker chromosome. The 10p amplicon contained 62 genes, including oncogenes such as MLLT10, previously described in chimeric fusion with MLL in leukemias, NEBL, and BMI1.

Schmitt J, Fischer U, Heisel S, et al.
GAS41 amplification results in overexpression of a new spindle pole protein.
Genes Chromosomes Cancer. 2012; 51(9):868-80 [PubMed] Free Access to Full Article Related Publications
Amplification is a hallmark of many human tumors but the role of most amplified genes in human tumor development is not yet understood. Previously, we identified a frequently amplified gene in glioma termed glioma-amplified sequence 41 (GAS41). Using the TCGA data portal and performing experiments on HeLa and TX3868, we analyzed the role of GAS41 amplification on GAS41 overexpression and the effect on the cell cycle. Here we show that GAS41 amplification is associated with overexpression in the majority of cases. Both induced and endogenous overexpression of GAS41 leads to an increase in multipolar spindles. We showed that GAS41 is specifically associated with pericentrosome material. As result of an increased GAS41 expression we found bipolar spindles with misaligned chromosomes. This number was even increased by a combined overexpression of GAS41 and a reduced expression of NuMA. We propose that GAS41 amplification may have an effect on the highly altered karyotype of glioblastoma via its role during spindle pole formation.

Teicher BA
Searching for molecular targets in sarcoma.
Biochem Pharmacol. 2012; 84(1):1-10 [PubMed] Related Publications
Sarcoma are about 1% of cancers. Within that 1% are widely varied tumors now divided into types and subtypes. Sarcoma occur in patients of all ages with frequency spread evenly over the human age range. Although the specific cell of origin of many sarcoma remains unclear, sarcoma are all tumors of mesenchymal origin. The mesenchymal stem cell, a pluripotent cell, which gives rise to varied differentiated cells including osteocytes, adipocytes, chondrocytes, muscle cells, fibroblasts, neural cells and stromal cells, is the most likely ultimate cell of origin for sarcoma. When mesenchymal stem cell genetics go awry and malignant transformation occurs sarcoma including osteosarcoma, Ewing's sarcoma, chondrosarcoma, rhabdomyosarcoma, synovial sarcoma fibrosarcoma, liposarcoma and many others can initiate. Our knowledge of sarcoma genetics is increasing rapidly. Two general groups, sarcoma arising from chromosomal translocations and sarcoma with very complex genetics, can be identified. Genes that are frequently mutated in sarcoma include TP53, NF1, PIK3CA, HDAC1, IDH1 and 2, KDR, KIT and MED12. Genes that are frequently amplified in sarcoma include CDK4, YEATS4, HMGA2, MDM2, JUN, DNM3, FLT4, MYCN, MAP3K5, GLI1 and the microRNAs miR-214 and miR-199a2. Genes that are upregulated in sarcoma include MUC4, CD24, FOXL1, ANGPTL2, HIF1α, MDK, cMET, TIMP-2, PRL, PCSK1, IGFR-1, TIE1, KDR, TEK, FLT1 and several microRNAs. While some alterations occur in specific subtypes of sarcoma, others cross several sarcoma types. Discovering and developing new therapeutic approaches for these relentless diseases is critical. The detailed knowledge of sarcoma genetics may allow development of sarcoma subtype-targeted therapeutics.

Piccinni E, Chelstowska A, Hanus J, et al.
Direct interaction of Gas41 and Myc encoded by amplified genes in nervous system tumours.
Acta Biochim Pol. 2011; 58(4):529-34 [PubMed] Related Publications
In order to understand better the role of the human Tip60 complex component Gas41, we analysed its expression levels in brain tumours and searched for possible interactors. Two-hybrid screening of a human foetal brain library allowed identification of some molecular interactors of Gas41. Among them we found n-Myc transcription factor. The interaction between Gas41 and n-Myc was validated by pull-down experiments. We showed that Gas41 is able to bind both n-Myc and c-Myc proteins, and that the levels of expression of Gas41 and Myc proteins were similar to each other in such brain tumors as neuroblastomas and glioblastomas. Finally, in order to identify which region of Gas41 is involved in the interaction with Myc proteins, we analysed the ability of Gas41 to substitute for its orthologue Yaf9 in yeast; we showed that the N-terminal portions of the two proteins, containing the YEATS domains, are interchangeable, while the C-terminal portions are species-specific. In fact we found that Gas41 C-terminal portion is required for Myc protein interaction in human.

Barretina J, Taylor BS, Banerji S, et al.
Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy.
Nat Genet. 2010; 42(8):715-21 [PubMed] Free Access to Full Article Related Publications
Soft-tissue sarcomas, which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States, show remarkable histologic diversity, with more than 50 recognized subtypes. However, knowledge of their genomic alterations is limited. We describe an integrative analysis of DNA sequence, copy number and mRNA expression in 207 samples encompassing seven major subtypes. Frequently mutated genes included TP53 (17% of pleomorphic liposarcomas), NF1 (10.5% of myxofibrosarcomas and 8% of pleomorphic liposarcomas) and PIK3CA (18% of myxoid/round-cell liposarcomas, or MRCs). PIK3CA mutations in MRCs were associated with Akt activation and poor clinical outcomes. In myxofibrosarcomas and pleomorphic liposarcomas, we found both point mutations and genomic deletions affecting the tumor suppressor NF1. Finally, we found that short hairpin RNA (shRNA)-based knockdown of several genes amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4, decreased cell proliferation. Our study yields a detailed map of molecular alterations across diverse sarcoma subtypes and suggests potential subtype-specific targets for therapy.

Fischer U, Keller A, Leidinger P, et al.
A different view on DNA amplifications indicates frequent, highly complex, and stable amplicons on 12q13-21 in glioma.
Mol Cancer Res. 2008; 6(4):576-84 [PubMed] Related Publications
To further understand the biological significance of amplifications for glioma development and recurrencies, we characterized amplicon frequency and size in low-grade glioma and amplicon stability in vivo in recurring glioblastoma. We developed a 12q13-21 amplicon-specific genomic microarray and a bioinformatics amplification prediction tool to analyze amplicon frequency, size, and maintenance in 40 glioma samples including 16 glioblastoma, 10 anaplastic astrocytoma, 7 astrocytoma WHO grade 2, and 7 pilocytic astrocytoma. Whereas previous studies reported two amplified subregions, we found a more complex situation with many amplified subregions. Analyzing 40 glioma, we found that all analyzed glioblastoma and the majority of pilocytic astrocytoma, grade 2 astrocytoma, and anaplastic astrocytoma showed at least one amplified subregion, indicating a much higher amplification frequency than previously suggested. Amplifications in low-grade glioma were smaller in size and displayed clearly different distribution patterns than amplifications in glioblastoma. One glioblastoma and its recurrencies revealed an amplified subregion of 5 Mb that was stable for 6 years. Expression analysis of the amplified region revealed 10 overexpressed genes (i.e., KUB3, CTDSP2, CDK4, OS-9, DCTN2, RAB3IP, FRS2, GAS41, MDM2, and RAP1B) that were consistently overexpressed in all cases that carried this amplification. Our data indicate that amplifications on 12q13-21 (a) are more frequent than previously thought and present in low-grade tumors and (b) are maintained as extended regions over long periods of time.

Italiano A, Bianchini L, Keslair F, et al.
HMGA2 is the partner of MDM2 in well-differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon.
Int J Cancer. 2008; 122(10):2233-41 [PubMed] Related Publications
Data concerning the fine structure of the 12q13-15 amplicon which contains MDM2 and CDK4 in well-differentiated and dedifferentiated liposarcomas (WDLPS/DDLPS) are scarce. We investigated a series of 38 WDLPS/DDLPS using fluorescence in situ hybridization analysis with 17 probes encompassing the 12q13-15 region. In addition, using quantitative RT-PCR we studied the expression of MDM2, CDK4, DDIT3 (CHOP/GADD153), DYRK2, HMGA2, TSPAN31 and YEATS4 (GAS41) in 11 cases. We showed that CDK4 (12q14.1) belonged to a distinct amplicon than MDM2 (12q15). There was no continuity in the amplified sequences between MDM2 and CDK4. Moreover, while MDM2 was amplified and overexpressed in all cases, CDK4 was not amplified or overexpressed in 13% of cases. The centromeric border of the CDK4 amplicon was located immediately downstream the 5' end of DDIT3, a gene known for being involved in myxoid liposarcoma translocations. DDIT3 was amplified in 3 cases and overexpressed in 9 cases. The overexpression of DDIT3 was correlated to the CDK4 amplification and not to its own amplification status. This suggested that the CDK4 amplicon, as well as the overexpression of DDIT3, might be generated by the disruption of a fragile region in 5' DDIT3. HMGA2 was always amplified and rearranged indicating that it plays a central role in WDLPS/DDLPS. HMGA2 rearrangement frequently resulted in a loss of the 3' end region that is a binding site for let-7. We also found a frequent amplification and overexpression of YEATS4, an oncogene that inactivates P53, suggesting that YEATS4 might play an important role together with MDM2 in WDLPS/DDLPS oncogenesis.

Persson F, Olofsson A, Sjögren H, et al.
Characterization of the 12q amplicons by high-resolution, oligonucleotide array CGH and expression analyses of a novel liposarcoma cell line.
Cancer Lett. 2008; 260(1-2):37-47 [PubMed] Related Publications
The cytogenetic hallmark of well-differentiated liposarcoma (WDLS) is a giant marker chromosomes containing amplified genes from chromosome 12q13-q15. Here, we have employed SKY and high-resolution 244K oligonucleotide array CGH to characterize rearrangements and amplifications in a new WDLS cell line (GOT3) with a giant marker chromosome derived from chromosomes 12, 1, and X. The most prominent amplifications included 144 genes in 12q11-q21.2, 201 genes in 1q23.3-q44, and six genes in 13q32.1-q32.2. In the 12q amplicons, MDM2 showed the highest level of amplification followed by LYZ, HMGA2 (5'-part), TSPAN8, CNOT2, YEATS4, CDK4, GNS, HELB, and TSFM. Expression analysis of genes from the three major amplicons revealed that several highly amplified potential target genes, including HMGA2, MDM2, YEATS4, CDK4, PKP1, IPO9, and SOX21, were strongly overexpressed. Studies of cell cycle controlling proteins that interact with CDK4 and MDM2 revealed an abnormally strong expression of cyclins D1 and E. The selective high-level amplification of the 5'-part of HMGA2, including the DNA-binding domains, suggests that this gene is a major target of amplifications in WDLS. Our results also identify several novel candidate genes of potential pathogenetic and therapeutic importance for WDLS.

Lauffart B, Gangisetty O, Still IH
Molecular cloning, genomic structure and interactions of the putative breast tumor suppressor TACC2.
Genomics. 2003; 81(2):192-201 [PubMed] Related Publications
The human transforming acidic coiled-coil 2 (TACC2) gene has been suggested recently to be a putative breast tumor suppressor. Now we can report the cloning of full length TACC2 cDNAs corresponding to the major isoforms expressed during development. The TACC2 gene is encoded by 23 exons, and spans 255 kb of chromosome 10q26. In breast cancer cell lines, TACC2 is expressed as a 120 kDa protein corresponding to the major transcript expressed in the mammary gland. Although only slight differences in the expression of TACC2 in normal versus breast tumors were observed, overexpression of TACC2 can alter the in vitro cellular dynamics of some breast cancer cell lines. Significantly, we demonstrate that TACC2 interacts with GAS41 and the SWI/SNF chromatin remodeling complex. This suggests that defects in TACC2 expression may affect gene regulation, thus contributing to the pathogenesis of some tumors.

Lauffart B, Howell SJ, Tasch JE, et al.
Interaction of the transforming acidic coiled-coil 1 (TACC1) protein with ch-TOG and GAS41/NuBI1 suggests multiple TACC1-containing protein complexes in human cells.
Biochem J. 2002; 363(Pt 1):195-200 [PubMed] Free Access to Full Article Related Publications
Dysregulation of the human transforming acidic coiled-coil (TACC) proteins is thought to be important in the evolution of breast cancer and multiple myeloma. However, the exact role of these proteins in the oncogenic process is currently unknown. Using the full-length TACC1 protein as bait to screen a human mammary epithelial cDNA library, we have identified two genes that are also amplified and overexpressed in tumours derived from different cellular origins. TACC1 interacts with the C-terminus of both the microtubule-associated colonic and hepatic tumour overexpressed (ch-TOG) protein, and the oncogenic transcription factor glioma amplified sequence 41/NuMA binding protein 1 (GAS41/NuBI1; where NuMA stands for nuclear mitotic apparatus protein 1). This suggests that the TACC proteins can form multiple complexes, dysregulation of which may be an important step during tumorigenesis.

Fischer U, Heckel D, Michel A, et al.
Cloning of a novel transcription factor-like gene amplified in human glioma including astrocytoma grade I.
Hum Mol Genet. 1997; 6(11):1817-22 [PubMed] Related Publications
Gene amplification, which is generally considered to occur late in tumor development, is a common feature of high grade glioma. Up until now, there have been no reports on amplification in astrocytoma grade I. In this study, we report cloning and sequencing of a cDNA termed glioma-amplified sequence (GAS41) which was identified recently in a glioblastoma cell line by microdissection-mediated cDNA capture. This technique is tailored to isolate amplified genes from human tumors. An increased copy number of GAS41 was found in glioblastoma multiforme and astrocytoma III, and at a high frequency in astrocytoma grades I and II. Sequence comparison indicates a high homology between the GAS41 protein, the yeast and human AF-9 and the human ENL proteins. Both AF-9 and ENL belong to a new class of transcription factors, indicating that GAS41 might also represent a transcription factor. With GAS41 being the first gene found with increased copy number in low grade glioma, this study provides the first evidence that gene amplification can occur in early tumor development.

Fischer U, Meltzer P, Meese E
Twelve amplified and expressed genes localized in a single domain in glioma.
Hum Genet. 1996; 98(5):625-8 [PubMed] Related Publications
Gene amplification has been associated both with tumor stage and progression in human gliomas. Several distinct amplified loci have been identified by comparative genomic hybridization and Southern blot analysis. It has been increasingly recognized that amplified domains comprise multiple genes. Here, we demonstrate amplification of up to 12 different genes from an amplified domain at 12q13-15 that has been found in approximately 15% of astrocytomas and glioblastomas. The amplified genes were GLI, WNT1, MDM2, SAS, CDK4 OS-4, GAS16, GAS27, GAS41, GAS56, GAS 64 and GAS89. In one glioblastoma all 12 amplified genes were also found to be expressed. These results strongly warrant the search for as yet unidentified genes in regions previously reported to be amplified.

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