bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-34: Investigating novel biological functions of tankyrases in cancer
Authors: Schoumacher Marie , Feng Yun , Mishina Yuji , Shao Wenlin 
Published: August 2012

Abstract
Tankyrases (TNKS1 and TNKS2) are enzymes that catalyze the addition of poly(ADP-riboses) on acceptor proteins. Through poly(ADP-ribosylation), TNKS regulate the activity and/or stability of their substrates via different mechanisms. A number of TNKS substrate proteins of diverse biological functions have been reported. More recently, in silico analysis using consensus-derived TNKS binding motif predicts a wide range of proteins may be targeted by TNKS, supporting that TNKS is involved in the regulation of diverse cellular processes. In particular, TNKS have been linked to telomere elongation, Wnt signaling and spindle assembly during mitotic progression, functions that are essential for cell proliferation. Hence, TNKS could be potential molecular targets for anti-cancer therapeutics. Using highly potent and specific TNKS inhibitors or depletion of TNKS by RNAi, we have identified several cancer models which growth is dependent on TNKS activity. In one of the TNKS-dependent cancer models, RERF-LC-MS, our studies demonstrate depletion of β-catenin does not impair cell proliferation. These data suggest TNKS regulate cell proliferation in this model via Wnt-independent functions. In an effort to elucidate the mechanism underlying RERF-LC-MS growth dependence on TNKS, we tested the hypothesis whether TNKS inhibition leads to aberrant spindle formation. We observed that inhibition of TNKS increases the formation of multipolar spindles in mitotic cells. We are currently testing whether this is mediated by NuMA, a well described substrate of TNKS whose function is required for spindle integrity. In addition, we are performing proteomic studies to identify novel binding partners of TNKS that would help to unravel novel partners of TNKS in mitosis and their functions in mediating cancer cell dependence on TNKS. Overall, this work will further increase our understanding of TNKS biology in cancer, and will impact on how we could best target TNKS as a novel anti-cancer treatment.
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 LB-34. doi:1538-7445.AM2012-LB-34
Abstract LB-341: Cysteine dioxygenase 1 is a tumor suppressor gene silenced by promoter methylation in multiple human cancers
Authors: Brait Mariana , Ling Shizhang , Nagpal Jatin , Chang Xiaofei , Park Hannah , Lee Juna , Okamura Jun , Yamashita Keishi , Sidransky David , Kim Myoung Sook 
Published: August 2012

Abstract
The human cysteine dioxygenase 1 (CDO1) gene is a non-heme structured, iron-containing metalloenzyme involved in the conversion of cysteine to cysteine sulfinate, and plays a key role in taurine biosynthesis. In our search for novel methylated gene promoters, we have analyzed differential RNA expression profiles of colorectal cancer (CRC) cell lines with or without treatment of 5-aza-2′-deoxycytidine. Among the genes identified, the CDO1 promoter was found to be differentially methylated in primary CRC tissues with high frequency compared to normal colon tissues. In addition, a statistically significant difference in the frequency of CDO1 promoter methylation was observed between primary normal and tumor tissues derived from breast, esophagus, lung, bladder and stomach. Downregulation of CDO1 mRNA and protein levels were observed in cancer cell lines and tumors derived from these tissue types. Expression of CDO1 was tightly controlled by promoter methylation, suggesting that promoter methylation and silencing of CDO1 may be a common event in human carcinogenesis. Moreover, forced expression of full-length CDO1 in human cancer cells markedly decreased the tumor cell growth in an in vitro cell culture and/or an in vivo mouse model, whereas knockdown of CDO1 increased cell growth in culture. Our data implicate CDO1 as a novel tumor suppressor gene and a potentially valuable molecular marker for human cancer.
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 LB-341. doi:1538-7445.AM2012-LB-341
Abstract LB-350: EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition by vemurafenib
Authors: Corcoran Ryan B. , Ebi Hiromichi , Turke Alexa B. , Coffee Erin M. , Nishino Michiya , Cogdill Alexandra P. , Brown Ronald D. , Dias-Santagata Dora , Pelle Patricia Della , Hung Kenneth E. , Flaherty Keith T. , Piris Adriano , Wargo Jennifer A. , Settleman Jeffrey , Mino-Kenudson Mari , Engelman Jeffrey A. 
Published: August 2012

Abstract
Oncogenic BRAF mutations occur in 10-15% of colorectal cancers (CRCs) and confer adverse outcome. While RAF inhibitors such as vemurafenib (PLX4032) have produced dramatic response rates in BRAF mutant melanoma (∼60-80%), they are surprisingly ineffective in BRAF mutant CRCs (∼5% response rate), and the reason for this disparity remains unclear. Compared to BRAF mutant melanoma cells, BRAF mutant CRC cells were less sensitive to vemurafenib, and P-ERK suppression was not sustained in response to treatment. Although transient inhibition of phospho-ERK by vemurafenib was observed in CRC, rapid ERK re-activation occurred through EGFR-mediated activation of RAS and CRAF. BRAF mutant CRC cell lines and patient tumor specimens expressed higher levels of phospho-EGFR than BRAF mutant melanoma cell lines and primary tumor specimens, suggesting that CRCs are specifically poised for EGFR-mediated resistance. Combined RAF and EGFR inhibition blocked reactivation of MAPK signaling in BRAF mutant CRC cells, markedly improved efficacy in vitro, and led to robust tumor regressions in vivo in BRAF mutant xenografts models. These findings support combined RAF and EGFR inhibition as a novel and promising therapeutic strategy for evaluation in clinical trials in patients with BRAF mutant 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 LB-350. doi:1538-7445.AM2012-LB-350
Abstract LB-359: Extended accumulation of acetylated histone in tumor tissues obtained from the phase I study of CG200745
Authors: Ro SeongGu , Kong Gyoung-Sun , Lee Sang-Koo , Cho Joong Myung , Cha Hyun-Ju , Kwon Sool Ki , Chang Ho-Jin , Kim Kyu-pyo , Hong Yong Sang , Bae Kyun-seop , Lee Jae-Lyun , Kim Tae Won 
Published: August 2012

Abstract
Extended Accumulation of Acetylated Histone in Tumor Tissues Obtained from the Phase I Study of CG200745 Accumulation of acetylated histone is a physiological phenomenon caused by inhibition of HDACs. We have observed such accumulation in cells, mice and humans when CG200745, our cancer therapeutic candidate, was treated. In the phase I clinical trial (NCT01226407), we had a chance to compare such accumulations in both the blood and tumor tissues. Interestingly, the accumulation in the tissues was maintained much longer than that in the blood and its level was significantly high even at 24 hours after dose. Such difference in histone accumulation has been explained by the different PK profile of CG200745 between the blood and the tumor tissues. Although we have not got PK data from the human tumor tissues yet, the difference was already observed in mice PK studies. Specifically, the half-life of CG200745 in plasma of mice was extremely short like other known HDAC inhibitors (approximately 20 mins), but in tumor tissues, that of CG200745 was as long as approximately 7 hours. In the current human studies, CG200745 is showing a much better PK profile in plasma than that of mice studies. Its half-life even in plasma is observed as several hours and clearance is much lower than other HDAC inhibitors. Actually, the AUC/dose of CG200745 is the highest among all the clinical stage HDAC inhibitors. Taking the extended accumulation of acetylated histone in the tumor tissues and better human PK profile into consideration, we believe that CG200745 with excellent HDAC inhibition will be a promising anticancer intervention in the near future.
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 LB-359. doi:1538-7445.AM2012-LB-359
Abstract LB-364: The ACRBP tumor antigen normalizes mitotic spindle function to promote cancer cell proliferation
Authors: Wehn Amy K. , Xie Yang , Schorge John O. , Whitehurst Angelique W. 
Published: August 2012

Abstract
Tumor cells can undergo a productive mitosis despite the wholesale presence of chromosomal aberrations. While this behavior may generate plasticity with respect to the acquisition of tumorigenic traits, it also represents a vulnerability for therapeutic intervention. Using a whole genome siRNA screen for modifiers of chemoresponsiveness, we identified the tumor antigen ACRBP/OY-TES-1 as a specifier of paclitaxel resistance. ACRBP is as a cancer-testis antigen, a class of genes whose expression is selective to the testes but frequently activated in a wide range of tumors. Scant functional data exists on the contribution of CT-antigens to tumorigenic phenotypes. Here, we find that ACRBP is both necessary and sufficient for paclitaxel resistance in ovarian cancer cell lines and ovarian tumor explants. Furthermore, depletion of ACRBP significantly sensitizes ovarian tumor cells to paclitaxel in an orthotopic xenograft model system. We identified the mitotic spindle component NuMA as an ACRBP-interacting protein that may account for the effects of ACRBP on paclitaxel sensitivity. In particular, ACRBP depletion results in mitotic errors and reduced proliferative fitness that can be rescued by NuMA co-depletion. ACRBP appears to modulate NuMA protein levels, potentially by regulating its post-translational modifications. Remarkably, NuMA overexpression, a frequent event in tumors, is sufficient to induce expression of ACRBP. We propose that activation of ACRBP is positively selected for during tumor evolution to buttress mitotic spindle fidelity and chromosome segregation. Identification and elaboration of elements of the genome that are subverted to support essential cell biological processes in tumor cells present new therapeutic opportunities.
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 LB-364. doi:1538-7445.AM2012-LB-364
Abstract LB-368: Exploiting the mechanism of intron-splicing to produce viral vectors harboring toxin genes for cancer therapy
Authors: Chen Haifeng 
Published: August 2012

Abstract
Suicide gene therapy has been widely investigated for the treatment of human immunodeficiency virus (HIV) infection, for controlling graft-versus-host disease, and also for the treatment of cancer. While the production of viral vectors carrying suicide genes such as the herpes simplex virus thymidine kinase (HSV-TK) or cytosine deaminase are easily achievable, the generation of viral vectors containing toxin genes such as diphtheria toxin A fragment (DT-A), Pseudomonas exotoxin (PE), and barnase has always been a challenge very difficult to fulfill due to the extreme toxicity of these toxins. We developed a novel way to produce in insect cells baculoviral and adeno-associated viral (AAV) vectors harboring toxin genes such as DT-A or Barnase by exploiting the different intron-splicing mechanisms between insect and mammalian cells. Since most of the mammalian introns are not functional in insect cells, we cloned two mammalian introns to interrupt the DT-A or Barnase coding sequences and produced recombinant baculoviral and AAV vectors at the normal level as compared with the baculoviral or AAV vectors carrying just the green fluorescent protein (GFP) gene. After transduction of the toxin gene-harboring baculoviral or AAV vectors into mammalian HEK293 cells, the mammalian introns were spliced out and toxins expressed and killed the HEK293 cells. This is the first report so far as we know that the differences in intron-splicing between insect and mammalian cells can be utilized to manufacture viral vectors harboring toxin genes. Our finding indicates that this novel method provides a valuable new tool for the development of toxin-based suicide gene cancer therapy. Bac, baculovirus; AAV, adenoassociated virus; inDTA (hGH), DT-A gene interrupted by human growth hormone intron; inBar (SV40)-GFP, Barnase gene interrupted by SV40 LT antigen intron and fused in-frame with GFP; vg, vector genome copy number; pfu, plaque-forming unit; ND, not done.
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 LB-368. doi:1538-7445.AM2012-LB-368
Abstract LB-378: The outlier approach discriminates drivers from passengers among genes methylated in cancers
Authors: Kikuyama Mizuho , Takeshima Hideyuki , Kinoshita Takayuki , Okochi-Takada Eriko , Wakabayashi Mika , Akashi-Tanaka Sadako , Ogawa Toshihisa , Seto Yasuyuki , Ushijima Toshikazu 
Published: August 2012

Abstract
A large number of genes are methylated in cancers, and most of them are methylated as passengers of carcinogenesis, and this fact hampers identification of drivers, tumor-suppressor genes (TSGs), silenced by aberrant methylation of promoter CpG islands (CGIs). To overcome this issue, we focused on the rule that the vast majority of genes methylated in cancers lack, in normal cells, RNA polymerase II (Pol II) and have trimethylation of histone H3 lysine 27 (H3K27me3) in their promoter CGIs. However, approximately 5% of the genes methylated in cancers are against this general rule, constituting a group of “outliers”. It is expected that TSGs belong to this group of outliers since they are expressed or ready to be expressed in normal cells. Here, we aimed to demonstrate that TSGs belong to the group of outliers, and that searching for outliers enables us to identify TSGs. First, we demonstrated that some of known TSGs in breast and colon cancers had Pol II and lacked H3K27me3 in normal cells, being outliers of the rule. We then made a genome-wide search for outlier genes in breast cancers. Based on Pol II binding and H3K27me3 statuses in normal cells and DNA methylation statuses in five breast cancer cell lines, 14 outlier genes were identified from 280 methylated genes. Among these genes, four genes were confirmed to be methylated in primary breast cancer samples, and two (HOXA5 and FBN2) of these were known TSGs. Among the remaining two genes, DZIP1 was shown to suppress growth of breast cancer cells, suggesting it to be a novel TSG. These results showed that some of known TSGs are the outlier genes and that TSGs can be efficiently identified by searching for outliers against the rule, the outlier approach.
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 LB-378. doi:1538-7445.AM2012-LB-378
Abstract LB-38: Kure It cancer research
Authors: Jones Karen 
Published: August 2012

Abstract
Kure It funds researchers conducting innovative projects in the fields of kidney cancer and other underfunded malignancies. Kiure It raised funds in several ways: through annual special events; contributions from family and community foundations; and partnerships with the self storage industry, through which we've created tailored programs and events aimed at raising funding and awareness. Since its inception in 2007, Kure It has raised over one milliion for research. The goal is to raise one million annually going forward. Kure It supports the work of researchers at City of Hope and Cedars-Sinai.
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 LB-38. doi:1538-7445.AM2012-LB-38
Abstract LB-381: Biochemical characterization of recombinant β-glucosyltransferase and analysis of global 5-hydroxymethylcytosine in unique genomes
Authors: Terragni Jolyon 
Published: August 2012

Abstract
5-hydroxymethylcytosine (5-hmC) is an enzymatic oxidative product of 5-methylcytosine (5-mC). Ten Eleven Translocation (TET) family of enzymes catalyze the conversion of 5-mC to 5-hmC. Phage encoded glucosyltransferases are known to glucosylate 5-hmC, which can be utilized to detect and analyze the 5-hmC an epigenetic mark in the mammalian epigenome. Here we have performed a detailed biochemical characterization and steady-state kinetic parameter analysis of T4 phage β-glucosyltransferase (β-GT). Recombinant β-GT glucosylates 5-hmC DNA in a non-processive manner and binding to either 5-hmC DNA or uridine diphosphoglucose (UDP-glucose) substrates is random, with both binary complexes being catalytically competent. Product inhibition studies with β-GT demonstrated that UDP is a competitive inhibitor to UDP-glucose and a mixed inhibitor to 5-hmC DNA. Similarly, the glucosylated-5-hmC (5-ghmC) DNA is a competitive inhibitor to 5-hmC DNA and mixed inhibitor to UDP-glucose. 5-hmC DNA binds ∼10 fold stronger to the β-GT enzyme when compared to its glucosylated product. The numbers of 5-hmC on target sequences influenced the turnover numbers for recombinant β-GT. Furthermore, we have utilized recombinant β-GT to estimate global 5-hmC content in a variety of genomic DNAs. Most of the genomic DNAs derived from vertebrate tissue/cell-lines contained 5-hmC. DNA from mouse, human and bovine brains displayed 0.5 to 0.9% of the total nucleotides as 5-hmC, which was higher compared to other tissues. A comparison between cancer and healthy tissue genomes suggested a lower percentage of 5-hmC in cancer, which may reflect the global hypomethylation of 5-mC observed during oncogenesis.
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 LB-381. doi:1538-7445.AM2012-LB-381
Abstract LB-384: BARX1, CYGB, and other epigenetic targets of gastric cancer
Authors: Agarwal Rachana , Mori Yuriko , Cheng Yulan , Abraham John M. , Montgomery Elizabeth , Meltzer Stephen J. 
Published: August 2012

Abstract
Gastric cancer (GC), a disease with a very poor prognosis, is the second leading cause of cancer-related deaths worldwide. Although few studies have identified genetic and epigenetic alterations to be involved in gastric carcinogenesis, the molecular pathogenesis of this disease remains incompletely understood, and largely unexplored. With an aim to understand, and identify the molecular pathways important in the pathogenesis of GC, and to identify targets for its detection and therapy, we conducted a pilot microarray-based genome-wide search for identification of epigenetic targets in GC. This study identified 11 prioritized targets of aberrant epigenetic inactivation in gastric neoplasia (GN), including the tight junction protein claudin-11 (CLDN11), the transcription factor BarH-like homeobox (BARX1), basonuclin1 (BNC1), Coagulation factor C homolog (COCH), filamin C gamma (FLNC), cytoglobin B (CYGB), glutamine-fructose-6-phospahe-transaminase-2 (GFPT2), heat-shock-70 kDa protein-6 (HSPA6), snail homolog 1(SNAL1), skin calmodulin-related factor (SCARF), and tumor protein p53 binding protein 2 (TP53BP2). Our initial validations of these targets, particularly, CLDN11, BARX1 and CYGB confirmed these genes to be hypermethylated in their promoter region in gastric cancer cell lines and patient specimens, and their mRNA expression levels to be reduced in gastric cancer tissues and cell lines. More interestingly, our recent preliminary studies demonstrate that overexpression of the BARX1, in GC cells which lack its endogenous expression led to dramatic phenotypic changes in these transfected cells. Moreover, viable cell count was reduced in BARX1 transfected cells. BARX1 is a transcription factor which is known to be involved in the differentiation of embryonic endoderm into stomach. This study for the first time, identifies a potential role of BARX1 in gastric carcinogenesis. Further, large-scale validation studies are underway to confirm the role of BARX1 and other genes as potential targets for GC detection and therapy.
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 LB-384. doi:1538-7445.AM2012-LB-384
Abstract LB-386: The NuRD complex cooperates with DNMTs to maintain silencing of colorectal tumor suppressor genes.
Authors: Cai Yi , Geutjes Ernst-Jan , Roepman Paul , Yu Li-Rong , Blijswijk Janneke V. , Wang Wei , Mohammad Helai , de Rink Iris , Baylin Stephen , Bernards Rene 
Published: August 2012

Abstract
Many Tumor Suppressor Genes (TSGs) are silenced through synergistic layers of epigenetic regulation including abnormal DNA hypermethylation of promoter CpG islands, repressive chromatin modifications and enhanced nucleosome deposition over transcription start sites. Many of the protein complexes responsible for silencing of such TSGs remain to be identified. A subset of silenced TSGs controlling key regulatory signaling pathways in colorectal cancer cells can be partially reactivated by in cells disrupted for the DNA methyltransferase 1 and 3B (DNMT1 and 3B) or by DNMT inhibitors (DNMTi). Herein, we used proteomic and functional genomic approaches to identify additional proteins that cooperate with DNMTs in silencing these key silenced TSGs in colon cancer cells. We discovered that DNMTs and the core components of the NuRD nucleosome remodeling complex, chromo domain helicase DNA-binding protein 4 (CHD4), histone deacetylases 1 and 2 (HDAC1 and 2), occupy the promoters of several of these key hypermethylated TSGs and physically and functionally interact to maintain their silencing. Consistent with this, we find an inverse relationship between expression of HDAC1 and 2 and these TSGs in a large panel of primary colorectal tumors. We demonstrate that this DNMT-NuRD complex maintains the silencing of several negative regulators of the WNT signaling pathway. We find that depletion of CHD4 is synthetic lethal with DNMT inhibition in correlation with reactivation of TSGs, suggesting that their combined inhibition may be beneficial for the treatment of colon cancer.
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 LB-386. doi:1538-7445.AM2012-LB-386