bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1070: Epigenetic silencing of galectin-12 in colorectal cancer
Authors: Katzenmaier Eva-Maria , Gebert Johannes , Kloor Matthias , Kopitz Jürgen 
Published: August 2015

Abstract
Aim/Background: Galectins constitute a family of ß-galactoside binding proteins some of them known to be involved in colorectal tumorigenesis. Our previous work suggests that sodium butyrate can induce galectin-12 expression in CRC cell lines. How this might be exerted is largely unexplored. In the present study we examined the potential epigenetic regulation of galectin-12 expression in colorectal cancer cell lines and primary tumors.
Material and Methods: For DNA-methylation analysis 4 microsatellite unstable (MSI) and 5 microsatellite stable (MSS) human CRC cell lines were treated with 5-Aza-2`deoxycytidine (5-Aza-dC) for 72h. Changes in galectin-12 expression were evaluated by RT-PCR analysis. Galectin-12 promoter methylation was determined by bisulfite treatment and genomic DNA sequencing of single clones in the CRC cell line SW707 as well as in FFPE specimens from 10 primary colorectal tumors (MSI: n = 5; MSS: n = 5).
Results: Treatment with 5-Aza-dC led to de novo expression of galectin-12 transcript in 4/9 (44%) of colorectal cancer cell lines. We identified a CpG island in the galectin-12 promoter region that was found to be hypomethylated upon 5-Aza-dC treatment in SW707 cells and to be associated with concomitant de novo galectin-12 mRNA expression. When primary tissues were examined we observed galectin-12 promoter hypomethylation in healthy colon mucosa but significant hypermethylation of this promoter region in corresponding tumor tissue.
Conclusions: This study for the first time shows that galectin-12 promoter methylation represses galectin-12 expression in colorectal tumor cells independent of their MSI status. In CRC cell lines this effect can be reversed by butyrate but in human colon primary tumors might be refractory to these effects of butyrate. Re-expression of galectin-12 may be a potential therapeutic strategy to constrain colorectal tumor growth.
Citation Format: Eva-Maria Katzenmaier, Johannes Gebert, Matthias Kloor, Jürgen Kopitz. Epigenetic silencing of galectin-12 in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1070. doi:10.1158/1538-7445.AM2015-1070
Abstract 108: Inhibition of demethylase, JMJD3 sensitizes diffuse large B-cell lymphoma (DLBCL) to chemotherapy
Authors: Mathur Rohit , Sehgal Lalit , Berkova Zuzana , Neelapu Sattva S. , Samaniego Felipe 
Published: August 2015

Abstract
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma (NHL) representing more than 30% of new cases diagnosed in the United States. DLBCL comprises multiple biologically and clinically distinct subtypes including germinal center B-cell-like (GCB) and activated B-cell like (ABC) DLBCL. Despite improvement in current therapies, nearly 40% of patients die from the disease. Recent studies of the epigenome and the methylome in particular, have revealed widespread epigenetic changes in DLBCL. Aberrant methylation of core histone tails occur with deregulation of methylase enzymes such as Ezh2 in DLBCL. In contrast, the role of JMJD3 and UTX, H3K27(me)3 demethylases in DLBCL remains unknown. In this study, we have evaluated the activity of the selective JMJD3 inhibitor GSK-J4 in DLBCL and investigated the mechanism of its action.
Methods
Panel of DLBCL cell lines: DB, KARPAS 422, Pfeiffer, Toledo, Sudhl2, Sudhl6, Sudhl8, TMD8, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly8, OCI-Ly4, OCI-Ly10, and primary DLBCL cells were analyzed for the expression of lysine demethylases (KDMs) using RT-PCR and Western blot analysis. Sub-G1 analysis was performed to analyze drug-induced apoptosis. Chemical inhibitor GSK-J4 and siRNAs were used for specific inhibition of the JMJD3.
Results
JMJD3 inhibitor, GSK-J4 induced the killing of DLBCL cell lines of both GC and ABC subtypes. Cell sensitivity to GSK-J4 could not be predicted from the expression of prognostic markers in DLBCL such as Bcl6, IRF4 and Ezh2. For further studies, we selected a cell line Sudhl6 (Bcl6 dependent), sensitive to the killing effect of GSK-J4. Treatment with GSK-J4 reduced the Bcl6 levels along with concomitant increase in IRF4 and FBXO11, negative regulators of Bcl6. Knockdown of JMJD3 by siRNAs also reduced the levels of Bcl6, implicating Bcl6 in the mechanism of action of GSK-J4. Additionally, GSK-J4 synergized in killing with vincristine, doxorubicin as well as proteasome inhibitors bortezomib and carfilzomib.
Conclusion
We demonstrate the potent effects of inhibition of H3K27(me)3 demethylase JMJD3 by GSK-J4 on proliferation and apoptosis of DLBCL cells. Our results clearly show synergistic effects of inhibition of demethylase with standard drugs in elimination of DLBCL cells.
Note: This abstract was not presented at the meeting.
Citation Format: Rohit Mathur, Lalit Sehgal, Zuzana Berkova, Sattva S. Neelapu, Felipe Samaniego. Inhibition of demethylase, JMJD3 sensitizes diffuse large B-cell lymphoma (DLBCL) to chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 108. doi:10.1158/1538-7445.AM2015-108
Abstract 1092: Interpreting and navigating the TCGA in the context of the RAS pathway
Authors: Yi Ming , Kessing Bailey , Stephens Robert 
Published: August 2015

Abstract
Analysis of large cancer data sets such as “The Cancer Genome Atlas (TCGA)” and the “International Cancer Genome Consortium (ICGC) “ has demonstrated the involvement of members of the RAS signaling pathway across many different tumor types. In particular, KRAS mutations occur at high frequency in lung, colorectal and particularly pancreatic tumors. Here, we report an analysis of TCGA data examining several aspects of KRAS and RAS pathway biology in the context several of the different data types collected through TCGA. The findings include:
• A survey of the expression of the KRAS alternatively spliced isoforms across all of the available tumor types
• Enrichment analysis from differentially expressed genes from high and low expressing samples for the 4A isoform (or the 4A/4B ratio)
• Survival analysis for RAS pathway genes in the context of mutational and expression level status
• Analysis of mutations in genes from the RAS pathway across samples and tumor types Together, these findings demonstrate that large data sets like TCGA can be used to reveal novel insights into the function of key genes that play a role in the development, maintenance and progression of cancer.
Citation Format: Ming Yi, Bailey Kessing, Robert Stephens. Interpreting and navigating the TCGA in the context of the RAS pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1092. doi:10.1158/1538-7445.AM2015-1092
Abstract 1098: Epistasis analysis of the PTHLH region in European subjects of the iCOGS breast cancer GWAS suggest multiple genes may be implicated in its role in breast cancer
Authors: Freeman Adam N. , Henderson Michael A. , Martin T John , Makalic Enes , Kapuscinski Miroslaw K. , Schmidt Daniel , Hopper John 
Published: August 2015

Abstract
Parathyroid hormone-related protein (PTHrP), the product of the PTHLH gene, has long been implicated in breast cancer. Its expression is thought to favour and, potentially, facilitate metastasis to bone. Paradoxically, a prospective clinical study clinical suggests that its production in primary breast cancers is actually protective, affording a better prognosis than its absence. Multiple recent Genome-Wide Association Studies (GWAS) have confirmed a single susceptibility locus immediately upstream of the PTHLH gene to be associated with breast cancer. This was again reproduced in the recent iCOGS GWAS, which involved over 90,000 European subjects. In spite of a single SNP, rs10771399, being uniquely reported and reproduced by prior studies, comprehensive analysis of the region reveals multiple significant SNPs stretching for hundreds of kbp across the locus. Epistasis analysis of this region versus the entire iCOGS array was performed using Plink!. These results suggest multiple genes may be implicated in the causation of this signal. Many known functional partners of PTHLH were identified, including IPO8, RUNX1, RUNX3, S100P, SOX9, SOX11, and SOX14. Multiple putative functional partners of PTHLH were likewise identified, including PBXIP1, PMVK, KCNN3, STX12, PPP1R8, CAMTA1, PRKCZ, TGIF1, SPHKAP, MYC, and STAT3. When taken together, these results offer novel potential insights into the function of the locus at PTHLH in breast cancer that may be further investigated.
Citation Format: Adam N. Freeman, Michael A. Henderson, T John Martin, Enes Makalic, Miroslaw K. Kapuscinski, Daniel Schmidt, John Hopper. Epistasis analysis of the PTHLH region in European subjects of the iCOGS breast cancer GWAS suggest multiple genes may be implicated in its role in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1098. doi:10.1158/1538-7445.AM2015-1098
Abstract 1100: Functional genomics to investigate the genetic determinants of cell death induced by oxidative stresses
Authors: Ding Chien-Kuang C. , Tang Xiaohu , Kim So Young , Chi Jen-Tsan A. 
Published: August 2015

Abstract
Increased oxidative stress in the tumor microenvironments is a prominent stress that many tumor cells need to cope with during oncogenesis. The stress depletes intracellular glutathione, increases reactive oxygen species, and finally triggers cell death in tumors. Despite its importance during oncogenesis, the genetic determinants and the cell death mechanisms under oxidative stress remain poorly defined. Here, we applied a genome-wide siRNA screen to oxidative-stress-induced cell death. Candidate genes were identified if the silencing could rescue cell death under oxidative stresses. The identified candidate genes are prioritized by the magnitude of rescue and the consistency among different siRNAs that target the same gene. Selected top hits were further functionally validated using independent siRNAs and chemicals in multiple cancer cell types. To further understand the functional aspects of these genes, we also analyzed the transcriptional and metabolomic response to oxidative stresses. By these functional genomics approach, we found that: 1) The Integrated Stress Response (ISR) is provoked by oxidative stresses to mediate cell death. Therefore, inhibition of IRE1-splicing activity, which is one of the major branches of ISR pathway, could abolish oxidative-stress-induced cell death. 2) Surprisingly, inhibition of multiple component of mTORC1 signaling, including mTOR itself, could rescue oxidative-stress-induced cell death. While further investigation is still in progress, these preliminary findings unravel a unique molecular process in which oxidative stress mediate cell death and the adaptive mechanism by which tumor cells survive these stresses.
Citation Format: Chien-Kuang C. Ding, Xiaohu Tang, So Young Kim, Jen-Tsan A. Chi. Functional genomics to investigate the genetic determinants of cell death induced by oxidative stresses. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1100. doi:10.1158/1538-7445.AM2015-1100
Abstract 1107: In whole-exome sequencing analysis, alternations of P-selectin glycoprotein ligand 1 (SELPLG) significantly associates with inflammation and survival outcomes
Authors: Cho Sunghoon , Lee Chansu , Choi Hyun , Ahn Kwang-Sung , Koh Yongil , Yoon Sung-Soo 
Published: August 2015

Abstract
SELPLG is type I transmembrane receptor found on the surface of neutrophils, monocytes, and most lymphocytes. SELPLG interacts with P -selectin mediates the tethering and rolling of neutrophils, monocytes, and/or lymphocytes on endothelial cells. In whole exome sequencing analysis, we found that somatic mutation of SELPLG (2%) was found. Also its alternation (37%) was found in germline control group. rs201851784 of SELPLG polymorphism (43%) was determined in 118 adult AML patients and its polymorphism (12%) was determined in 1000 genome. The prevalence of the rs201851784 polymorphism was significantly different between AML patients and normal control (AA genotype vs. GG + AG genotype). Comparison analysis of SELPLG showed X-squared = 208.4140, df = 1 and p &lt; 2.2e-16. After the IL-6 expression levels among AML patients were detected by ELISA, the allelic status and IL-6 expression on bone marrow serum of AML patients were analyzed. AML patient having A/G alternation was found to be associated with lower levels of IL-6 compared with AML patients having A/A. Those with persistence had higher IL-6 expression levels compared with those with CR in 1st induction (P &lt; 0.05). In addition, there is a significant correlation between levels and SELPLG rs201851784, as analyzed by linear correlation assay. The AA genotype correlated with higher IL-6 levels (P &lt; 0.05). Reverse correlation between SELPLG rs201851784 and IL-6 levels was found. SELPLG rs201851784 and IL-6 levels were also significantly correlated with OS. In conclusion, a polymorphism in the SELPLG gene related to cell dissemination and tissue infiltration is shown for the first time to be associated with susceptibility of AML and the overall survival.
Citation Format: Sunghoon Cho, Chansu Lee, Hyun Choi, Kwang-Sung Ahn, Yongil Koh, Sung-Soo Yoon. In whole-exome sequencing analysis, alternations of P-selectin glycoprotein ligand 1 (SELPLG) significantly associates with inflammation and survival outcomes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1107. doi:10.1158/1538-7445.AM2015-1107
Abstract 113: Defining the metabolic regulation of epigenetics using chemical proteomics
Authors: Meier Jordan L. , Montgomery David C. , Sorum Alexander W. , Kulkarni Rhushikesh A. 
Published: August 2015

Abstract
Substantial evidence indicates that chromatin modifiers are sensitive to changes in the cellular concentration of metabolites and cofactors. These findings potentially connect metabolism and gene expression, and have major implications for the regulation of cell signaling in cancer. However, missing from many of these studies has been the direct identification of the specific chromatin modifiers that sense change in metabolic state. Their identification is critical to our basic understanding of how metabolism regulates epigenetically-driven phenotypes, and may inform novel strategies to restore balance in metabolically-perturbed cancers. Towards this goal, here we report a strategy to directly define the metabolic regulation of epigenetic signaling using chemical proteomics. Our initial efforts have focused on understanding the metabolic regulation of lysine acetyltransferases (KATs), a major class of chromatin modifiers responsible for protein acetylation. We demonstrate that chemoproteomic probes can report on the interaction of acyl-CoA metabolites with KAT active sites, and when combined with affinity purification and LC-MS/MS analysis, highlight an expanded landscape of acetyltransferases present in the human genome. Next-generation chemoproteomic methods highlight the interactions of metabolic acyl-CoAs with megadalton lysine acetyltransferase protein complexes, which have implications for the regulation of KAT activity by cellular acyl-CoA pools. By defining the molecular links connecting metabolism and gene expression,these approaches will illuminate our understanding of cancer biology and inspire new therapeutic strategies to combat cancer.
Citation Format: Jordan L. Meier, David C. Montgomery, Alexander W. Sorum, Rhushikesh A. Kulkarni. Defining the metabolic regulation of epigenetics using chemical proteomics. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 113. doi:10.1158/1538-7445.AM2015-113
Abstract 1142: COP1 functions as a sensor of cellular lipids and regulator of lipogenesis in human cancer cells
Authors: Huang Chenfei , Bu Yiwen , Cao Deliang 
Published: August 2015

Abstract
Background
Constitutive photomorphogenesis protein 1 (COP1; also known as Rfwd2), an evolutionally conserved E3 ubiquitin ligase, has been defined to mediate the degradation of several important proteins, such as p53, c-Jun, ETS, FOXO1 and ACC1, being involved in tumorigenesis. In response to DNA damage, COP1 is autodegraded in the context of ATM, which is triggered by 14-3-3σ. However, the biological function and expression regulation of COP1 remain to be fully understood. This study reports a novel function of COP1 in lipid metabolism.
Methods
We targeted COP1 expression in cancer cells MCF-7 and HepG2 with COP1 shRNA lentivirus and COP1 overexpression lentivirus, respectively. We investigated the lipid synthesis, glucose oxidation and conversion into lipids in these cells using radiolabeled acetate and glucose and lipid complex analysis. Quantitative real-time PCR and Western blot were used to examine gene expression. Acetyl CoA carboxylase-1 (ACC1) siRNA and TOFA, an inhibitor of ACC1, were used to modulate the intracellular lipid synthesis.
Results
Lipid depletion induced by acetyl CoA carboxylase-1 (ACC1) knockdown or the inhibition of ACC1 by TOFA induced COP1 expression, but palmatic acid, the end-product of de novo fatty acid synthesis pathway, reversed TOFA-induced COP1 expression. In addition, U73122, an inhibitor of phospholipase C that cleaves PIP2 into DAG and IP3, triggered COP1 expression. These data suggest that COP1 expression is mediated by cellular lipid state, and the lipid second messengers (PIP2 and DAG) are involved in the expression regulation of COP1. In contrast, the ectopic expression of COP1 greatly reduced pAMPK and pACC1 levels, but elevated fatty acid synthase (FASN) expression, leading to the increase of fatty acid (FA)/lipid synthesis. In sharp contrast, siRNA-mediated COP1 knockdown in cancer cells significantly increased pACC1 and pAMPK levels and reduced FASN expression, leading to decrease of lipid synthesis. The cell growth and proliferation was accordingly changed in response to the alterations of lipid synthesis. Altogether our data suggest that COP1 expression is regulated through the lipid second messenger mediated signaling, and the upregulated COP1 in turn enhances lipid synthesis, functioning as a positive feedback.
Conclusion
COP1 functions as a sensor of cellular lipid state and promoter of lipogenesis, facilitating tumorigenesis.
Note: This abstract was not presented at the meeting.
Citation Format: Chenfei Huang, Yiwen Bu, Deliang Cao. COP1 functions as a sensor of cellular lipids and regulator of lipogenesis in human cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1142. doi:10.1158/1538-7445.AM2015-1142
Abstract 1145: The TDP-43 confers resistance to metabolic stress condition via activating autophagy in GBM cells
Authors: Lin Tzu-Wei , Wu Chen-Wen 
Published: August 2015

Abstract
Glioblastoma (GBM) is the most aggressive malignant brain tumor in adults. TDP-43 (TARDBP), a DNA and RNA binding protein, is well known to play a key role in RNA processing, including involving in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Recent reports suggested that TDP-43 participate to the regulation of metabolic glycolysis in cancer. Overcoming metabolic stress is critical for cancer cell survival and growth in nutrient deprivation condition. Herein we found protein level of TDP-43 was increased in nutrient deprivation. Overexpression TDP-43 promotes glioblastoma cell survival and suppressed the activated-form levels of caspase 3 protein under nutrient deprivation. Overexpression of TDP-43 increased the tumorigenicity as determined by anchorage-independent growth assay and xenografts in immunocompromised mice model. Under nutrient deprivation, we also found that TDP-43-overexpression induced autophagy. Recent evidence suggests that autophagy is a cell survival mechanism in cancer cells. Finally, treatment of autophagy inhibitor blocks the survival of TDP-43 overexpressing GBM cells in nutrient deprivation condition. By this study, we presume TDP-43 enhanced GBM cells tumorigincity, activated autophagy and inhibited cell death under nutrient deprivation condition. TDP-43 is potentially the new aspects for understanding the tumorigenicity and metablolic regulation for malignant brain tumors and GBM.
Citation Format: Tzu-Wei Lin, Chen-Wen Wu. The TDP-43 confers resistance to metabolic stress condition via activating autophagy in GBM cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1145. doi:10.1158/1538-7445.AM2015-1145