bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1036: Antiproliferative effects of DNA methyltransferase 3B depletion are not associated with DNA demethylation
Authors: Stresemann Carlo , Hagemann Sabine , Mund Cora , Kuck Dirk , Prinz Florian , Brueckner Bodo , Mumberg Dominik , Lyko Frank , Sommer Anette 
Published: August 2012

Abstract
Silencing of genes by DNA hypermethylation contributes to cancer progression and has been shown to occur with increased frequency at specific genomic loci. However, the precise mechanisms underlying the establishment and maintenance of aberrant methylation marks are still elusive. The de novo DNA methyltransferase 3B (DNMT3B) has been suggested to play an important role in the generation of cancer-specific methylation patterns. Previous studies have shown that a reduction of DNMT3B protein levels induces antiproliferative effects in cancer cells that were attributed to the demethylation and reactivation of tumor suppressor genes. However, methylation changes after depletion of DNMT3B protein have not been analyzed in detail yet. We performed short- and long-term RNAi knockdown experiments to reduce DNMT3B protein levels in colon cancer cell lines and analyzed genome-wide DNA methylation changes on HumanMethylation27 and HumanMethylation450 Illumina bead chips. Our results confirm that depletion of DNMT3B specifically reduced the proliferation rate of DNMT3B-overexpressing colon cancer cell lines. All colon cancer cell lines tested contain a mutant K-Ras and we conclude that K-Ras status - in contrast to DNMT3B protein overexpression levels - does not impact on anti-proliferative responses after DNMT3B knockdown. However, in contrast to the dramatic alterations of DNA methylation observed in DNMT1; DNMT3B double knockout cells (DKO), genome-scale DNA methylation profiling failed to reveal methylation changes at putative DNMT3B target genes, even in the complete absence of DNMT3B. These results show that DNMT3B is dispensable for the maintenance of aberrant DNA methylation patterns in human colon cancer cells and they have important implications for the development of targeted DNA methyltransferase inhibitors as epigenetic cancer drugs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1036. doi:1538-7445.AM2012-1036
Abstract 1042: Down-regulation of UTX contributes to lung cancer progression
Authors: Gilbert Jennifer L. , Maresh Erin , Mah Vei , Gower Adam , Goodglick Lee , Gomperts Brigitte 
Published: August 2012

Abstract
Smoking, the main risk factor leading to lung cancer, causes both genetic and epigenetic changes resulting in aberrant gene expression. UTX is a histone demethylase that has been implicated in many cancers and has been shown to regulate both cell cycle and differentiation genes. However, the role of UTX has not been elucidated in lung cancer. We hypothesized that smoking injury leads to a down regulation in UTX expression. This results in an inability of repairing airway epithelial cells to differentiate, resulting in premalignant lesions and ultimately invasive lung cancer. Examination of published lung cancer data sets revealed a down-regulation of Utx gene expression in patients with poorer prognosis, tumor grade, tumor recurrence and in smokers. To assess the involvement of UTX protein expression in lung cancer we stained a lung cancer tissue microarray and found a significant correlation between down-regulation of UTX protein expression and poorer prognosis in metastasis (p=0.0005) and smokers (p= 0.02). UTX expression was found to be significantly lower in squamous cell carcinoma compared to adenocarcinoma, linking down-regulation of UTX in a diseased caused solely by smoking. To test if smoking directly affects Utx expression we treated mouse airway epithelial cells at air-liquid interface with media infused with cigarette smoke for 9 days. After this short time point of acute smoke exposure there was a significant down regulation of Utx gene expression (p=0.03). We carried out UTX overexpression studies to assess the role of UTX in lung cancer cells lines and found up-regulation of UTX results in up-regulation of genes involved in lung development and differentiation, including Nrf2, FoxJ2 and FZD4. Our finding support the hypothesis that smoking causes a reduction in UTX that affects the proliferation and differentiation of airway epithelial cells contributing to lung cancer progression. Re-activation of UTX therefore may be a potential therapeutic target for the prevention of lung cancer progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1042. doi:1538-7445.AM2012-1042
Abstract 105: Characterizing the exomic profile of MSI colorectal cancer
Authors: Kondelin Johanna K. , Gylfe Alexandra , Tuupanen Sari , Ristolainen Heikki , Katainen Riku , Tanskanen Tomas , Jarvinen Heikki , Mecklin Jukka-Pekka , Vahteristo Pia , Aaltonen Lauri A. 
Published: August 2012

Abstract
Colorectal cancer (CRC) is the third most common cancer in Western countries. Of all CRC tumors, 15% display microsatellite instability (MSI) caused by defective cellular mismatch repair. Cells displaying MSI accumulate a high number of mutations throughout the genome, especially in short repeat areas called microsatellites. Also point mutations occur in excess in these tumors. Sporadic MSI CRCs are caused by biallelic inactivation of the MLH1 gene, usually by promoter hypermethylation. The MSI tumors have a genetic and clinopathological profile that significantly differs from microsatellite stable (MSS) CRC. Overall, MSI tumors have been studied much less than MSS tumors, mainly due to the high number of mutations in MSI tumors, which makes data analysis and identification of relevant mutations challenging. To date, several genes have been proposed as MSI target genes based on targeted searches of their mutation frequency in microsatellite areas. A few systematic sequencing studies on colorectal cancer have been published, but none of them focus on MSI tumors, making this study first of a kind. In this study, the exome of 25 sporadic MSI tumors and corresponding normal samples are sequenced to identify changes of somatic origin. Bioinformatical tools are used to rank the genes and identify true driver genes based on clustering of missense mutations. The most interesting findings will be validated by direct Sanger sequencing. In addition to corresponding normal specimens, samples from healthy Finnish blood donors as well as data from other ongoing sequencing projects and sequence databases are used as controls to exclude polymorphisms. The data of all the 25 tumors has been analyzed and validation of the potential clusters of missense mutations is in process. The pathological nature of the changes will be confirmed by possible functional studies. This way we wish to identify new driver genes in MSI CRC. A detailed understanding of the molecular background of this tumor type is important for the development of more efficient screening methods and personalized treatments. By characterizing changes typical for different MSI tumors, we wish to identify subtypes within the MSI tumor category that could be exploited in treatment. Such understanding of MSI tumors could improve the treatment and hence prognosis of patients diagnosed with MSI type CRC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 105. doi:1538-7445.AM2012-105
Abstract 1051: UHRF1 is highly expressed in childhood liver tumors and interacts with DNMT1 and USP7 to guide tumor suppressor gene silencing
Authors: Trippel Franziska , Joppien Saskia , Felle Max , Längst Gernot , Kappler Roland 
Published: August 2012

Abstract
Embryonal tumors are thought to arise from immature tissue during intrauterine or early postnatal development and display apart from specific genetic changes in developmental signaling pathways a relatively normal genomic background. Instead, epigenetic events appear to be involved in key steps of the earliest phases of neoplastic evolution. However, the mechanistic basis responsible for epigenetic alterations in these early-onset tumors and the role of the DNA methylation machinery therein is still not known. In order to define the impact of epigenetic factors in embryonal tumor development we made use of hepatoblastoma (HB), the most common liver tumor of early childhood, as a model for a pristine and genetically “clean” tumor. In this study we identified ubiquitin-like with PHD and ring finger domains 1 (UHRF1) to be highly overexpressed in HB tumors compared to normal liver tissue, a protein known to preferentially bind to hemi-methylated DNA. Using immunoprecipitation, we furthermore show that UHRF1 binds in concert with DNA methyltransferase 1 (DNMT1) and ubiquitin specific peptidase 7 (USP7) as a trimeric complex to promoter regions of tumor suppressor genes relevant in HB, such as hedgehog interacting protein (HHIP), insulin-like growth factor binding protein 3 (IGFBP3), and secreted frizzled-related protein 1 (SFRP1). These genes are epigenetically silenced in HB, as evidenced by heavy DNA methylation and enrichment of the repressive H4K27me3 chromatin mark. Interestingly, knockdown of UHRF1 expression via RNA interference resulted in promoter demethylation and a shift towards the active H3K4me2 chromatin mark of the three tumor suppressor genes. Altogether, these data suggest that aberrant expression of the epigenetic regulator UHRF1 and excessive binding of a trimeric complex consisting of UHRF1/DNMT1/USP7 results in silencing of tumor suppressor genes in HB and may display an important mechanism in the initial phases of embryonal tumorigenesis in general.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1051. doi:1538-7445.AM2012-1051
Abstract 1057: Mutation of EZH2 A677 in human B-cell lymphoma promotes hyper-trimethylation of H3K27
Authors: McCabe Michael T. , Graves Alan P. , Ganji Gopinath , Ott Heidi , Diaz Elsie , Halsey Wendy S. , Jiang Yong , Smitheman Kimberly N. , Pappalardi Melissa B. , Allen Kimberly E. , Chen Stephanie , Della-Pietra Anthony , Dul Edward , Hughes Ashley M. , Thrall Sara H. , Tummino Peter J. , Kruger Ryan G. , Brandt Martin , Schwartz Benjamin , Verma Sharad K. , Creasy Caretha L. 
Published: August 2012

Abstract
Trimethylation of histone H3 on lysine 27 (H3K27me3) is a repressive post-translational modification mediated by the histone methyltransferase EZH2. EZH2 is a component of the Polycomb Repressive Complex 2 (PRC2) and its expression and catalytic activity are dysregulated in cancers. While EZH2 may be over-expressed as a result of multiple mechanisms in tumors, only somatic mutation of the EZH2 Y641 residue has thus far been reported to alter its substrate preference and enhance its catalytic efficiency to generate H3K27me3. Herein, we report mutation of the A677 residue of EZH2 to a glycine (A677G) in a lymphoma cell line with aberrantly elevated H3K27me3 levels. Additional EZH2 sequence analysis in 41 primary lymphoma specimens identified another occurrence of this mutation. Biochemical evaluation of recombinant EZH2 complexes revealed that A677G EZH2 possesses catalytic activity with substrate specificity that is novel and distinct from those of wild-type and Y641 mutants. Whereas wild-type EZH2 displayed a preference for substrates with less methylation (i.e. H3K27me0&gt;me1&gt;me2), the Y641 mutants exhibited greatly decreased activity with H3K27me0 and increased activity with H3K27me2. The A677G EZH2, on the other hand, exhibited nearly equal efficiency for all three substrates. A677G EZH2, but not wild-type EZH2, was shown to be capable of significantly increasing global H3K27me3 when transiently expressed in an EZH2 wild-type cancer cell line. Finally, structural modeling suggests that the mutation results in a larger lysine tunnel capable of accommodating the H3K27me2 substrate while retaining the ability to properly orient H3K27me0 and H3K27me1 with the Y641 residue. In addition, functional and biochemical analyses are performed with reversible SAM-competitive EZH2 inhibitors. Therefore, this mutation appears to contribute to the aberrant epigenetic profile observed in certain lymphomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1057. doi:1538-7445.AM2012-1057
Abstract 1058: Mutations in isocitrate dehydrogenase 1 and 2 are associated with DNA hypermethylation in intrahepatic cholangiocarcinomas
Authors: Wang Pu , Dong Qiong-Zhu , Zhang Chong , Kuan Pei-Fen , Liu Yufeng , Jeck William R. , Andersen Jesper B. , Auman James Todd , Hoskins Janelle M. , Kim Jin Woo , Cibulskis Kristian , Getz Gad , Hunt Heike V. , Thorgeirsson Snorri S. , Roberts Lewis R. , Ye Dan , Guan Kun-Liang , Xiong Yue , Qin Lun-Xiu , Chiang Derek Y. 
Published: August 2012

Abstract
Cholangiocarcinomas are rare but aggressive cancers, with an increasing incidence and a dismal 5-year survival rate of less than 5%. Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in ∼70% of gliomas, ∼20% of myeloid leukemias, ∼56% of chondrosarcomas, and ∼10% of melanomas. We discovered IDH1 and IDH2 mutations in 29 of 305 (9%) intrahepatic cholangiocarcinomas. Tumors with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3K79. Mutations in IDH1 or IDH2 were independently associated with longer time to recurrence of cholangiocarcinoma in multivariate analysis (p = 0.046). We identified 2,267 genes that were significantly hypermethylated in tumors with mutations in IDH1 or IDH2. Hypermethylated CpG sites were significantly enriched in CpG shores and in the 1500 bp upstream of annotated transcription start sites, suggesting a global regulation of transcriptional potential. Gene expression profiling of 7 IDH1/2-mutant and 20 IDH1/2-wildtype tumors revealed increased expression of citric acid cycle and oxidative phosphorylation enzymes, as well as decreased expression of cytoskeleton organization genes. Integrated analyses of DNA methylation and gene expression identified interleukin-6 and several of its downstream targets as candidates for silencing by DNA methylation. Conclusions: Cholangiocarcinomas with mutations in IDH1 or IDH2 represent a molecular subclass with distinct signaling pathway alterations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1058. doi:1538-7445.AM2012-1058
Abstract 1062: Combinatorial expression of histone modifying enzymes differentiates Ewing's sarcoma family of tumors from mesenchymal stem cells and other sarcomas
Authors: Bennani-Baiti Idriss M. , Aryee Dave , Kovar Heinrich 
Published: August 2012

Abstract
Ewing's sarcoma family of tumors (ESFT) regroups mesenchymal tumors of bone and soft tissues that affect mostly children and young adults. ESFT is characterized by genetic lesions that include chromosomal translocations that generate de novo chimeric fusion oncoproteins between the TLS/EWS/TAF15 family of RNA-binding proteins and members of the ETS family of transcription factors. Contrary to the progress made in uncovering the genetic bases of Ewing's sarcoma, much remains to be discovered in the epigenetic mechanisms underlying ESFT pathogenesis. We have recently shown that alterations in the expression of EZH2 (a.k.a. KMT6), a methyltransferase that catalyzes the H3K27me3 mark, and of LSD1 (a.k.a. KDM1A), an H3K4me3 demethylase, contribute to ESFT pathology and can be targeted with drugs to curtail Ewing's sarcoma cell growth in vitro (EZH2 and LSD1) and in vivo (EZH2). To start deciphering the contribution of epigenetic modifiers to ESFT pathology, we surveyed the expression of all known histone modifying enzymes (HMEs) in four ESFT patient cohorts, totaling 96 tumors. We used the Ican analytical method to infer gene expression significance compared to a mesenchymal stem cell benchmark, as previously reported (Clin. Cancer Res 16: 3769-78, 2010). We show that, in addition to EZH2 and LSD1, several HMEs are up-regulated in ESFT compared to mesenchymal stem cell progenitors, indicating that the combinatorial activities of several HMEs are likely to promote an ESFT-specific epigenomic landscape. These findings represent the first extensive analysis of HMEs in ESFT, suggest a role of HMEs in ESFT pathogenesis and/or maintenance, and offer putative drug targets that may provide much needed novel ESFT epigenetic therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1062. doi:1538-7445.AM2012-1062
Abstract 1071: Epidermal growth factor induces anterograde lysosome trafficking via activation of p38
Authors: Dykes Samantha S. , Cardelli James A. 
Published: August 2012

Abstract
Previous studies from our laboratory have demonstrated that acidic extracellular pH and activation of c-Met by the Hepatocyte Growth Factor (HGF) in the tumor microenvironment, have the ability to induce anterograde (outward) lysosome trafficking in prostate tumor cells, resulting in an increase in protease secretion and tumor cell invasion. Lysosome redistribution requires microtubules, sodium proton exchangers (NHEs) and PI-3K activity. These processes can be blocked by preventing anterograde lysosome trafficking using NHE inhibitors or anti-diabetic drugs belonging to the thiazolidinedione class. Epidermal Growth Factor (EGF) is another growth factor that is commonly expressed in the tumor microenvironment, including prostate tumors, and is involved in activating a variety of processes leading to tumor progression. Upon binding of the EGF to Epidermal Growth Factor Receptor (EGFR), a variety of cellular survival and stress pathways are activated, ultimately resulting in cytoskeletal changes and altered gene expression that contribute to the increased motility and invasion of tumor cells. Interestingly, we have found that EGFR activation also induces anterograde lysosome trafficking and scattering in DU145 prostate cancer cells by a mechanism that is dissimilar to that of HGF-induced lysosome movement. For instance, we have determined that EGF anterograde lysosome trafficking and scattering is dependent on the activity of the mitogen activated protein kinase p38α, but is not dependent on the activity of PI3K. Conversely, HGF mediated lysosome trafficking and scattering is dependent on the activity of PI3K. Additionally, EGF induced peripheral lysosome movement appears to be independent of the activity of NHE 1 and 3, but treatment with the broad acting NHE inhibitor, EIPA [5-(N-ethyl-N-isopropyl)-amiloride], prevented EGF induced anterograde lysosome trafficking and promoted a clustering of lysosomes around the nucleus, suggesting that multiple NHEs are involved in EGF mediated lysosome trafficking. This was accompanied by a reduction in cell invasion through reconstituted basement membrane in a transwell invasion assay. Also, EGF-induced lysosome repositioning was reversed by troglitazone, an anti-diabetic agent. Together, these data further implicate lysosome positioning as critical to the process of HGF and EGF mediated tumor invasion and provide insight into the mechanism by which EGF induces peripheral lysosome trafficking. This information further supports the notion that inhibition of lysosome repositioning is a potentially viable therapeutic target to block HGF- and EGF-induced tumor cell invasion.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1071. doi:1538-7445.AM2012-1071
Abstract 1076: Ids act as downstream effectors in the transforming growth factor-β pathway in prostate cancer cells
Authors: Strong Nicole , Millena Cecille , Walker Lindsey , Chaudhary Jaideep , Khan Shafiq 
Published: August 2012

Abstract
Transforming growth factor-β (TGFβ) regulates proliferation, differentiation and differentiated function in a wide variety in cells. In prostate cancer cells, TGFβ inhibits proliferation in the earlier stages; however the cancer cells become refractory to growth inhibitory effects in advanced stages where TGFβ promotes cancer progression and metastasis. Intracellular mechanisms involved in these varied effects of TGFβ on prostate cancer cells are poorly understood. Inhibitor of Differentiation (Id) family of closely related proteins (Id1, Id2, Id3, Id4) inhibit binding of bHLH transcription factors to DNA and inhibit their effects on cell proliferation and differentiation. In the present study, we have investigated the involvement of Id1 and Id3 proteins in the effects of TGFβ on prostate cancer cells. Id1 and Id3 isoforms of protein are expressed in DU145 cells, which have previously been shown to be responsive to growth inhibitory effects of TGFβ. TGFβ caused a significant increase of protein levels of Id1 and Id3 as determined by Western blot analyses. This early induction was followed by a late downregulation of Id1, while Id3 induction remained stable. However in PC3 cells, this early induction of Id1 and Id3 proteins remained stable. Proliferation marker p21 was also induced in DU145 cells, while p21 protein was undetected in PC3 cells upon TGFβ1 treatment. Since previous studies have revealed that the loss of Id1 or Id3 is indicative of loss of proliferation in prostate cancer, Id1 effects were further studied between DU145 and PC3 cell lines. Id1 knockdown in DU145 cells resulted in enhanced inhibitory effects of TGFβ on cell proliferation. However, Id1 knockdown in PC3 did not influence TGFβ effects on proliferation. These results indicate that Id1 downregulation by TGFβ may be required for its effects on proliferation in DU145 cancer cells. We next investigated TGFβ effects on migration in PC3 cells, which TGFβ stimulation has been shown to increase its migration properties. Both Id1 and Id3 knockdown in PC3 cells decreased migratory response to TGFβ. This indicated that both Id1 and Id3 are necessary for TGFβ migratory properties of PC3 cells. Taken together, these results show that Id1 and Id3 act as necessary proteins in the TGFβ pathway on both proliferation and migration. Grant support: NIH 1P20MD002285-02 and RCMI G12RR03602
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1076. doi:1538-7445.AM2012-1076