bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4854: Inhibition of high-mobility group box 1 protein (HMGB1) release sensitizes cancer cells to chemotherapy
Authors: Tang Daolin , Kang Rui , Zeh Herbert J. , Lotze Michael T. 
Published: February 2011

Abstract
Metabolic and therapeutic stress can simultaneously provoke both adaptive and apoptotic responses in cancer cells. The sum of these programmed signals determines the fate of the cell: cell death or cell survival. As the catalogue of defects in pathways that control apoptosis in human tumors is expanding, understanding the significance of the alternative stress fate, autophagy, has become increasingly important. High-mobility group box 1 protein (HMGB1) is a highly conserved nuclear protein, acting as an architectural chromatin-binding factor that bends DNA and promotes protein assembly on specific DNA targets. In addition to its intranuclear roles, HMGB1 was also discovered recently to function as an extracellular signaling molecule during inflammation, cell differentiation, cell migration, and tumor metastasis. Ethyl pyruvate was first identified as an experimental agent that ameliorated inflammation, significantly reducing circulating levels of HMGB1 in animals with sepsis. Similarly, glycyrrhizin was identified as a direct small-molecule inhibitor of HMGB1 release and activity. To determine whether inhibition of HMGB1 release sensitizes cancer cells to chemotherapy, we pretreated cell with ethyl pyruvate or glycyrrhizin. These inhibitors attenuated melphalan-induced HMGB1 release. Moreover, inhibition of HMGB1 decreased autophagy by microtubule-associated protein 1 light chain 3 (LC3) puncta and LC3-II/p62 levels assay, and increased apoptosis by flow cytometry and cleaved-poly (ADP-ribose) polymerase (PARP) assays in Panc2.03 and HCT116 tumor cells when treated with chemotherapy. To further characterize the role of HMGB1 release in cancer cells following chemotherapy, a target-specific short hairpin RNA (shRNA) to HMGB1 was transferred into Panc2.03 and HCT116 tumor cells. Transfection of HMGB1-shRNA led to a significant decrease in HMGB1 protein as well as release in these cells. Depletion of HMGB1 by shRNA in these cells decreased autophagy and rendered them significantly more sensitive to melphalan-induced apoptotic cell death. Thust HMGB1 release links autophagy and apoptosis, and serves as a potential drug target for therapeutic intervention.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4854.
Abstract 4857: The role of autophagy in taxane resistant breast cancer models
Authors: Rechache Nesrin S. , Riggins Rebecca B. , Shajahan Ayesha N. , Zwart Alan , Clarke Robert 
Published: February 2011

Abstract
Treatment with the taxanes (Paclitaxel or Docetaxel) is often the therapy of choice for women with advanced breast cancer. In most cases, the taxanes can arrest cell proliferation at the G2/M phase and cause cell death. However, some tumors develop resistance during the course of treatment, which is a major concern for both patients and physicians. Several mechanisms have been proposed to explain how resistance to the taxanes occurs, but this phenomenon remains incompletely understood. We hypothesize that changes in cell death signaling, through apoptotic and non-apoptotic pathways, are responsible for taxane resistance in breast cancer. Using the MDA-MB-231 breast cancer cell line model, we selected cells that are resistant to either Docetaxel (DocR) or Paclitaxel (PacR). Subsequently we studied levels of cell death and the response to IC50 concentrations of these drugs. Given the molecular crosstalk that can occur between cells dying by apoptosis and the autophagy process, Western blots for prosurvival Bcl-2 and NFκB were performed, and these showed reduced expression in the taxane resistant cells compared to the sensitive cell lines. In conjunction with changes in apoptotic markers in the resistant cell lines, there were also changes in autophagy protein markers such as increased expression of cleaved LC3 and a decrease in p62/SQSTM1 expression, particularly in the PacR cells. Beclin-1 and XBP-1 expression, however, were not differentially expressed between the sensitive and both resistant cell lines. Beclin-1 and p62 have been implicated in the regulation of both Bcl-2 and NFκB expression. In order to determine whether the changes in autophagy marker protein expression was an indication of an alternative cell death process or cell survival, proliferation assays were performed with sensitive and resistant cells. Cells were counted after exposure for 7 days with and without 3-Methyladenine, an inhibitor of autophagosome formation. The addition of 3-MA significantly decreased cell number suggesting that autophagy may be a mechanism of cell survival in both taxane resistant models. Given our preliminary data, we propose to further investigate the role of autophagy and other alternative cell death evasion pathways seen in MDA-MB-231 taxane resistant and sensitive breast cancer cells. Our studies aim to improve the understanding of how different mechanisms of cell death evasion contribute to the resistance phenotype. Ultimately our studies may not only improve our understanding of taxane resistance at the bench, but may also provide the framework for formulation of novel therapies that may improve the success of taxane therapy in women with breast cancer in the clinic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4857.
Abstract 4873: Functional interactions between lysine 20 methylation and lysine 16 acetylation on histone H4 in DNA damage responses
Authors: Hsiao Kuei-Yang , Mizzen Craig 
Published: February 2011

Abstract
Individual histone post-translational modifications have been implicated in regulating many cellular events. Modifications can occur at high densities in the N-terminal tail domains of core histones, enabling the possibility that combinations of modifications regulate chromatin processes differently than modifications occurring individually. However, surprisingly little is known about the nature and functions of multi-site histone modification. This study investigates functional interactions between acetylation of lysine 16 (K16ac) and methylation of lysine 20 (K20me), two modifications that frequently occur together on molecules of histone H4. Methylation state-specific binding of p53-binding protein 1 (53BP1) to dimethyl K20 H4 (K20me2) and the formation of 53BP1 nuclear foci near double strand breaks are early events in DNA damage responses (DDR) that provide a platform for the assembly of downstream effectors. Since global levels of K20me2 are relatively stable and are established independently of DNA damage, we propose that reversible changes in the levels of K16ac co-modification act like a dynamic switch to modulate DDR responses mediated by K20me2. Analyses of the interaction of the K20me2 binding domain of 53BP1 with H4 peptides in vitro reveal that K16ac co-modification attenuates specific recognition of K20me1/2 by 53BP1. The possibility that K16ac and K20me2 interact functionally in vivo is demonstrated by our finding that K16 deacetylation accompanies the induction of H2AX phosphorylation, a well-known marker for DDR, following DNA damage by either UV irradiation or bleomycin treatment. Moreover, the effects of expressing K16 mutants of H4 and inhibition of histone deacetylases on 53BP1 foci formation induced by DNA damage are consistent with our hypothesis that K16ac co-modification negatively regulates the formation of 53BP1 foci. DDR mechanisms are frequently deregulated in cancer cells. Further investigation of the role of H4 modifications in DDR will enhance our understanding of how genome integrity is maintained in normal cells and may identify novel targets for future therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4873.
Abstract 4874: Epigenetic gene silencing is co-regulated by DNMT3B and polycomb-mediated histone modifications in human cancer
Authors: Jin Bilian , Robertson Keith D. 
Published: February 2011

Abstract
CpG-cytosine methylation, the only epigenetic modification in mammalian DNA, is established and maintained by three DNA methyltransferases (DNMT): DNMT1, DNMT3A, and DNMT3B. Although essential for development and differentiation, DNA methylation patterns are frequently disrupted in cancer and contribute directly to carcinogenesis. Recent studies linking polycomb group (PcG) repression complexes (PRC1 and PRC2) to the DNMTs have begun to shed light on how methylation is targeted. By comparing genes regulated by DNMT3B, which we identified in previous studies, with known polycomb group target genes, we chose a panel of genes co-regulated by DNMT3B and PRC1/PRC2 to test whether these criteria (DNMT & PcG co-regulation) could accurately identify novel targets of epigenetic silencing in human colon cancer. Using reverse transcription-PCR, bisulfite genomic sequencing, and pyrosequencing, we show that the majority of these genes are frequently silenced in colorectal cancer cell lines and primary tumors. We then analyzed the histone code, DNMT, and PRC1/PRC2 binding by chromatin immunoprecipitation at epigenetically silenced loci to reveal a novel link between DNMT3B and PRC1, which was further confirmed by siRNA knockdown assays. Specifically, loss of DNMT3B resulted in significant reductions in ubiquitinated histone H2A levels, a mark catalyzed by the RING2 subunit of PRC1. Taken together, these studies suggest that patterns of epigenetic modifiers and the histone code influence the propensity of a gene to become hypermethylated in cancer and that DNMT3B plays an important role in regulating PRC1 function.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4874.
Abstract 4882: Loss of p300 reduces miR-let-7c and enhances ER-positive breast cancer cell tumorigenicity
Authors: Yuan Huijun , Sil Sukanya , Sharma Salil , Bishopric Nanette 
Published: February 2011

Abstract
Histone deacetylase (HDAC) inhibitors have been extensively studied as potential anticancer treatments and several are currently in clinical trials. p300 is a nuclear histone acetyltransferase that is an important coordinator of multiple transcription-dependent cellular processes. HDAC inhibitors may directly and indirectly increase the activity of p300. The role of p300 is dependent on cell context but most or all of its biological activity stems from its ability to acetylate histones or non-histone nucleoproteins including p53, HSP) which regulate cell proliferation, differentiation and apoptosis. Whether p300 acts as a tumor suppressor or promoter is controversial, and its role in estrogen positive breast cancer remains to be defined, however, structural studies indicate that it has significant potential as a target for small molecule therapy. To address this issue, we have used a lentiviral approach to achieve 60-70% stable knockdown (KD) of p300 levels in estrogen receptor-positive breast cancer lines MCF-7 and BT 474 respectively. Growth curve and FACS analysis showed that loss of p300 shortened doubling times and increased G2 phase cells in both lines. Xenograft tumors formed from p300 KD cells were on average about three times larger at six weeks post implantation than control tumors (p&lt;0.05). H&E and CD31 staining showed that p300 KD xenograft tumors have a more aggressive phenotype with increased vascularity. In searching for targets of p300 that might regulate its anti-tumor effect, we observed that the microRNA miR-let-7c was downregulated in p300-depleted MCF-7 and BT474 cells. Consistent with this, the miR-let-7c target N-Ras was up-regulated in both p300 KD cell lines and in p300 KD xenograft tumors, and adenovirus-mediated over-expression of p300 caused downregulation of N-RAS. Finally, gene expression analysis showed that loss of p300 resulted in upregulation of E-cadherin, laminin, collagen, IL-6, IFN, TGF-β and components of the Wnt signaling pathway, indicating a shift from epithelial to mesenchymal phenotype. Our data show that p300 loss or inactivation results in altered transcription patterns and suppression of anti-tumor microRNAs, including let-7, and may induce a more invasive and potentially metastatic phenotype. We conclude that p300 likely acts as a tumor suppressor in breast cancer and that activation of p300 may contribute to the anti-tumor effects of TSA.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4882.
Abstract 4885: Changes of H3K9 modification by increased expression of HDAC2 and SUV39H1 modulates chromosome condensation in A549 lung cancer cells
Authors: Park Jin-Ah , Kim Ae-Jin , Lee Joo-Kyung , Ham Myoung-Sun , Kim Keun-Cheol 
Published: February 2011

Abstract
Genetic information is condensed from interphasic chromatin to mitotic chromosome for correct segregation into two daughter cells. Phosphorylation of H3S10 is well-known as modification marker for chromosome condensation, but further modification at several histone residues could be required for correct mitosis. In this study, we show that H3K9me3 was dramatically increased at mitotic cells, whereas H3K9ac was decreased. Chromosome spreading analysis is shown that H3K9me3 was distinctly increased at a longitudinal section of chromosome at prophase and prometaphase. These combinational modification of H3K9 was resulted from the increased expression of HDAC2 and SUV39H1, suggesting that these proteins are involved in chromosome condensation. Interestingly, FACS analysis is shown that metaphasic progression was delayed in HDAC inhibition by TSA treatment. Moreover, HDAC2 expression was increased from late S phase to M phase, and SUV39H1 expression was sequentially followed from G2 to M phase, implicating that activities of HDAC2 and SUV39H1 are modulated during chromosome condensation. Therefore, we suggest that increased expression of HDAC2 and SUV39H1 facilitate chromosome condensation targeting combinational modification of H3K9.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4885.
Abstract 4900: MAGE-A11 expression in castration-recurrent prostate cancer: association with a global epigenetic defect
Authors: James Smitha R. , Forti Lena D. , Mohler James L. , Wilson Elizabeth M. , Karpf Adam R. 
Published: February 2011

Abstract
Despite the initial clinical response to androgen deprivation therapy, most prostate cancer patients subsequently develop castration-recurrent disease. Elucidation of the mechanisms driving this process is expected to lead to improved strategies to prevent and treat advanced prostate cancer. Epigenetic alterations, including DNA hypomethylation, play a key role in human cancer development. DNA hypomethylation is thought to promote oncogenesis in part by driving oncogene expression, but its potential role in castration-recurrent prostate cancer is unknown. Melanoma Antigen A-11 (MAGE-A11) is a cancer germline (CG) antigen that stabilizes the androgen receptor (AR), facilitates AR association with co-activators, and promotes AR transcriptional activity; thus it appears to play an oncogenic role in castration-recurrent disease. We have recently reported that MAGE-A11 is over-expressed in prostate cancer cell lines, prostate cancer xenografts, and human prostate cancer tissues; in each setting MAGE-A11 overexpression is associated with DNA hypomethylation at the MAGE-A11 promoter CpG island (Karpf et al., Molecular Cancer Research 7; 523-535, 2009). Critically, MAGE-A11 expression and promoter hypomethylation correlate with castration-recurrent cancer growth, both in the CWR-22 xenograft model and in primary human prostate cancer tissues. In the current study we examined whether MAGE-A11 expression and hypomethylation in prostate cancer is an isolated molecular event, or alternatively whether it coincides with a global DNA hypomethylation defect. To test this, we analyzed the global DNA methylation status of prostate cancer cell lines, CWR-22 cancer xenografts, and primary prostate cancer, in which MAGE-A11 expression and methylation was also characterized. We assessed global DNA methylation by measuring total genomic 5-methyl-2′-deoxycytidine (5mdC), LINE-1 repetitive DNA element methylation, and the expression and methylation of several other CG antigen genes, including MAGE-A1, NY-ESO-1, XAGE-1, and BORIS/CTCFL. Taken together, our data provide evidence for a global DNA hypomethylation phenotype in castration-recurrent prostate cancers that express MAGE-A11. Ongoing studies are using HpaII tiny fragment enrichment by ligation-mediated PCR (HELP assay) to define the epigenome of castration-recurrent prostate cancer displaying MAGE-A11 expression. In summary, our data provide evidence that global DNA hypomethylation contributes to castration-recurrent prostate cancer, at least in part by promoting MAGE-A11 expression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4900.
Abstract 4903: Oxidative DNA damage and its relationship with GSTP1 methylation in prostate cancer
Authors: Fnu Rajnee , Sharma Haripaul , Gupta Sanjay 
Published: February 2011

Abstract
Prostate cancer is the most common cancer diagnosed in men and is the second leading cause of cancer-related death in the United States. The risk factor for prostate cancer includes both genetic and epigenetic modifications. Growing evidence suggests that epigenetic mechanisms such as DNA methylation affect gene expression in tissue-specific manner. The most frequent epigenetic alteration observed in human prostate cancer is hypermethylation of gluthathione-S-transferase-pi class (GSTP1) in the promoter region which causes loss or its decrease expression. Inactivation of GSTP1 renders prostate epithelial cells vulnerable to oxidative DNA damage from both oxidants and electrophile carcinogens to acquire relevant genetic alteration and neoplastic transformation. Extensive observations suggest that reactive oxygen species may cause accumulated DNA damage which might contribute to increased incidence of prostate cancer. However, the role of GSTP1 and its correlation with DNA damage has not been studied. Based on the assumption that DNA damage is prevalent in cancer cells compared to nontumorous tissue, we took a panel of 24 human prostate specimens obtained after surgery which comprised of matched primary tumor and adjacent nontumorous (benign) prostate tissues. Oxidative DNA damage was measured by 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels through highly sensitive and quantitative ELISA assay. GSTP1 methylation was determined by methyl-specific PCR and 5-methylcytosine estimation was performed by HPLC analysis. The 8-OHdG levels were higher in cancer specimen compared to their benign counterparts. The 8-OHdG levels in DNA of prostate cancer tissues ranged from 0.151 to 0.616ng/μg DNA, whereas the levels in benign tissue range from 0.149 to 0.318ng/μg DNA, respectively. The increase in 8-OHdG levels correlate with GSTP1 methylation which was higher in cancer specimens compared to the benign counterparts. Furthermore, levels of 5-methylcytosine were higher in tumor specimens compared to benign tissue. Taken together, our studies suggest that there is a link between GSTP1 methylation and DNA damage which correlates to epigenetic modification in prostate cancer. Our results are in agreement with the prediction that positive relationship occur between GSTP1 inactivation and DNA damage in prostate cancer.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4903.
Abstract 4913: The Bmi-1 polycomb protein antagonizes the (−)-Epigallocatechin-3-gallate dependent suppression of skin cancer cell survival
Authors: Balasubramanian Sivaprakasam , Adhikary Gautam , Eckert Richard L. 
Published: February 2011

Abstract
The Polycomb Group (PcG) proteins are epigenetic suppressors of gene expression that play a key role in promoting cell survival. This suppression is achieved via the action of two multiprotein PcG complexes - PRC2 (eed) and PRC1 (Bmi-1). These complexes act to modulate gene expression by increasing histone methylation and reducing acetylation - ultimately leading to a closed chromatin conformation and gene silencing. Activity of these proteins is associated with increased cell proliferation and survival. We show increased expression of key PcG proteins in immortalized keratinocytes and skin cancer cell lines. We examine the role of two key PcG proteins, Bmi-1 and Ezh2, and the impact of the active agent in green tea polyphenol, (−)-epigallocatechin-3-gallate (EGCG), on the function of these regulators. EGCG treatment of SCC-13 cells reduces Bmi-1 and Ezh2 level and this is associated with reduced cell survival. The reduction in survival is associated with a global reduction in histone H3-K27-trimethylation (H3 K27-3M), a hallmark of PRC2 complex action. This change in PcG protein expression is associated with reduced expression of key proteins that enhance progression through the cell cycle (cdk1, cdk2, cdk4, cyclin D1, cyclin E, cyclin A, and cyclin B1) and increased expression of proteins that inhibit cell cycle progression (p21 and p27). Apoptosis is also enhanced, as evidenced by increased caspase 9, 8 and 3 cleavage and increased PARP cleavage. EGCG treatment also increases Bax and suppresses Bcl-xL expression. Vector-mediated enhanced Bmi-1 expression reverses these EGCG-dependent changes. These findings suggest that green tea polyphenols reduce skin tumor cell survival by influencing PcG-mediated epigenetic regulatory mechanisms.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4913.