bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2297: 15-Deoxy-Δ12,14-prostaglandin J2 upregulates the expression of 15-hydroxyprostaglandin dehydrogenase through DNA methyltrasferase 1 inactivation
Authors: Jang Hye-Ok , Lee Ha-Na , Kim Areumnuri , Kim Do-Hee , Surh Young-Joon , Na Hye-Kyung 
Published: May 2015

Abstract
15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme that catalyzes the conversion of prostaglandin E2 to a biologically inactive keto metabolite. The down regulation of 15-PGDH is ubiquitously observed in various human malignancies including breast cancer. Hypermethylation of CpG islands present in the gene promoter region is considered to silence the expression of 15-PGDH. However, the molecular mechanisms underlying regulation of 15-PGDH remain largely unknown. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand of peroxisome proliferator-activated receptor γ, has been reported to have anti-inflammatory and anti-carcinogenic activities. In the present study, we have found that 15-PGJ2 upregulates expression and catalytic activity of 15-PGDH in human breast cancer (MDA-MB-231) cells. 15d-PGJ2 decreased the level of CpG methylation in the 15-PGDH promoter in MDA-MB-231 cells as determined by the bisulfite genome sequencing and methyl specific PCR. 15d-PGJ2 inhibited catalytic activity of methyltransferase 1 (DNMT1) but did not influence expression of either mRNA or protein of DNMT1. siRNA knockdown of DNMT1 induced expression of 15-PGDH. Biotinylated 15d-PGJ2 directly interacted with DNMT1 and reduced its catalytic activity. Chromatin-immunoprecipitation analysis revealed that 15d-PGJ2 significantly attenuated DNMT1 binding to the site for AP-1 transcription factor present in the 15-PGDH promoter regions. We also observed that 15-PGJ2 induced expression of c-Fos, but not c-Jun in the nuclear extract of MDA-MD-231 cells. Moreover, 15d-PGJ2 increased the c-Fos binding to the 15-PGDH promoter regions. A non-electrophilic analogue 9,10-dihydro-15d-PGJ2 failed to suppress the methylation of CpG islands present in 15-PGDH promoter and did not affect DNMT1 activity and 15-PGDH expression. This finding suggests that the α,β-unsaturated carbonyl group is essential for 15d-PGJ2-mediated inactivation of DNMT1 and expression of 15-PGDH. In conclusion, 15d-PGJ2 plays as a hypomethylating agent through direct interaction with DNMT1 and thereby suppresses DNMT1-mediated hypermethylation of 15-PGDH promoter, leading to upregulation of 15-PGDH expression.
Citation Format: Hye-Ok Jang, Ha-Na Lee, Areumnuri Kim, Do-Hee Kim, Young-Joon Surh, Hye-Kyung Na. 15-Deoxy-Δ12,14-prostaglandin J2 upregulates the expression of 15-hydroxyprostaglandin dehydrogenase through DNA methyltrasferase 1 inactivation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2297. doi:10.1158/1538-7445.AM2014-2297
Abstract 2307: DNA methylation as a reprogramming modulator: An epigenomic roadmap to induced pluripotency
Authors: Lee Dong-Sung 
Published: May 2015

Abstract
During cellular reprogramming to induced pluripotent stem cells (iPSCs), somatic cells rebuild their epigenetic architecture to acquire a steady self-renewing state. Here we systematically characterize the epigenomic roadmap to pluripotency by performing whole genome bisulfite sequencing of the “Project Grandiose” (PG) samples, along with analysis of histone modification and the transcriptome. The differentially methylated regions (DMRs) of the DNA samples revealed that hypermethylated-DMRs (Hyper-DMRs) gradually accumulated throughout reprogramming whereas there was a distinct gain in hypomethylated-DMRs (Hypo-DMRs) once cells reached the ESC-like state. ESC-associated transcription factor binding sites (ESC-TFBSs) were highly enriched in the Hypo-DMR group. During high transgene expression, leading to the pluripotent F-class state, cells exhibited focal DNA demethylation at the binding sites of the activated reprogramming factors, whereas ESC-like pluripotent cells exhibited widespread demethylation surrounding these sites. Genes associated with CpG rich promoters demonstrated a stable low DNA methylation state with strong engagement of H3K4me3 and H3K27me3 histone marks (histone modification-driven control). CpG poor promoter-related genes were repressed by DNA methylation, with transcriptional activity occurring upon promoter demethylation (DNA methylation-driven control). We further report that a proportion of genes proposed to be ESC-pluripotency predictors, including Dppa2, Eras, and Esrrb, are associated with CpG poor promoters and become transcriptionally activated upon DNA demethylation in ESC-like cells. Gene expression leading to ESC-like pluripotency is impacted and specifically orchestrated by dynamic changes of DNA methylation and histone modification. These results suggest that DNA methylation plays a crucial role within the epigenetic switch that drives somatic cells to pluripotency.
Citation Format: Dong-Sung Lee. DNA methylation as a reprogramming modulator: An epigenomic roadmap to induced pluripotency. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2307. doi:10.1158/1538-7445.AM2014-2307
Abstract 2311: NDN, an imprinted tumor suppressor gene inhibits ovarian cancer cell growth and motility and is downregulated by genetic and epigenetic mechanisms
Authors: Yang Hailing , Das Partha , Yu Yinhua , Baggerly Keith , Wang Ying , Mao Weiqun , Marquez Rebecca T. , Lu Zhen , Liu Jinsong , Bast Robert C. 
Published: May 2015

Abstract
NDN is a maternally imprinted gene on chromosome 15q11.2 that is consistently expressed in normal ovarian epithelium, but dramatically downregulated in the majority of ovarian cancer cell lines and surgical specimens, determined by gene expression array and RT-PCR analysis. On tissue microarrays, little or no NDN protein could be detected by immunohistochemical analysis in73% of 351 epithelial ovarian cancers. Loss of NDN expression could be attributed, in part, to LOH in 28% of 18 informative cases and to hypermethylation of CpG sites 1 and 2 in the NDN promoter region in 21% and 27% of 43 ovarian cancers, respectively. All hypermethylated cases were associated with NDN down-regulation. Promoter hypermethylation and decreased NDN expression were also found in 7 of 10 ovarian cancer cell lines. Treatment with the demethylating agent decitabine increased NDN expression in 4 of 7 hypermethylated cell lines. Treatment with the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) increased NDN expression in 2 cell lines with normal or reduced methylation. However, when the two drugs were combined, they didn't show additive or synergistic effect. Re-expression of NDN in ovarian cancer cell lines such as SKOv3 and HEY significantly inhibited cell growth, associated with apoptosis, but not autophagy or necrosis. Re-expression of NDN also inhibited cell migration. These observations support the hypothesis that NDN is an imprinted tumor suppressor gene and its loss of function can be caused by multiple mechanisms in ovarian cancer.
Citation Format: Hailing Yang, Partha Das, Yinhua Yu, Keith Baggerly, Ying Wang, Weiqun Mao, Rebecca T. Marquez, Zhen Lu, Jinsong Liu, Robert C. Bast. NDN, an imprinted tumor suppressor gene inhibits ovarian cancer cell growth and motility and is downregulated by genetic and epigenetic mechanisms. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2311. doi:10.1158/1538-7445.AM2014-2311
Abstract 2314: The combination of DNA methylation and H3K27me3 is a cancer-specific dual epigenetic modification
Authors: Takeshima Hideyuki , Wakabayashi Mika , Hattori Naoko , Yamashita Satoshi , Ushijima Toshikazu 
Published: May 2015

Abstract
Alterations of epigenetic modifications are promising targets of cancer therapy, and several epigenetic drugs are now used in the clinical field. At the same time, individual epigenetic modifications have physiological roles. Therefore, a cancer-specific combination of epigenetic modifications (dual modifications) is considered to be better as a therapeutic target. However, it is unclear whether or not such cancer-specific dual modification is present. In this study, we aimed to clarify whether cancer-specific dual modification is present by focusing on the combination of two major repressive modifications, DNA methylation and trimethylation of histone H3 lysine 27 (H3K27me3).
DNA methylation and H3K27me3 analyses in human colon, breast, and prostate cancer cell lines by Infinium HumanMethylation450 and ChIP-on-chip, respectively, revealed that 24.7±4.1% of DNA methylated genes were co-localized with H3K27me3 in cancer cells. In contrast, only 11.8±7.1% of DNA methylated genes were co-localized with H3K27me3 in their normal counterpart cells. 29.9±17.4% of genes with the dual modifications had neither DNA methylation nor H3K27me3 in normal counterpart cells. Expression levels of genes with the dual modifications were as low as those of genes with only DNA methylation in cancer cells. Analysis of re-activation of genes with the dual modifications by a DNA demethylating reagent, 5-aza-2′-deoxycytidine (5-aza-dC), and/or an EZH2 inhibitor, GSK126, revealed that genes with the dual modifications, such as IGFBP7, SFRP1, and SLC6A15, were re-activated more efficiently by the combination treatment than by a single treatment with 5-aza-dC. In contrast, such a combination effect on gene re-activation was not observed for genes with only DNA methylation. Furthermore, the combination treatment by 5-aza-dC and GSK126 had an additive inhibitory effect on growth of cancer cells.
These results showed that genes with the dual modifications, DNA methylation and H3K27me3, are increased in cancer cells, and the combination of a DNA demethylating reagent and an EZH2 inhibitor is useful for re-activation of these genes.
Citation Format: Hideyuki Takeshima, Mika Wakabayashi, Naoko Hattori, Satoshi Yamashita, Toshikazu Ushijima. The combination of DNA methylation and H3K27me3 is a cancer-specific dual epigenetic modification. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2314. doi:10.1158/1538-7445.AM2014-2314
Abstract 2316: Multilayer omics analyses in CpG island methylator phenotype clear cell renal cell carcinomas
Authors: Arai Eri , Sakamoto Hiromi , Ono Masaya , Takahashi Yoriko , Miyata Sayaka , Fujimoto Hiroyuki , Gotoh Masahiro , Yamada Tesshi , Kanai Yae 
Published: May 2015

Abstract
[Background] We have reported that CpG-island methylator phenotype (CIMP)-positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poorer patient outcome. We have established the criteria for CIMP diagnosis in clear cell RCCs by quantification of DNA methylation levels of RCC-specific CIMP marker genes.
[Purpose] The aim of this study was to reveal the molecular pathways which significantly participate in CIMP-positive renal carcinogenesis and become a therapeutic target of CIMP-positive clear cell RCCs.
[Methods] Our previous methylome analysis using Illumina Infinium HumanMethylation27 BeadArray identified CIMP-negative and -positive clear cell RCCs in the present cohort (n=101). In the present study, genome (whole-exome), transcriptome and proteome analyses using Agilent SureSelect All Exon capture followed by sequencing on an Illumina HiSeq 2000 platform, Agilent SurePrint Human Gene Expression microarray and two dimensional image converted analysis of liquid chromatography-mass spectrometry, respectively, were performed in tissue specimens of 87 CIMP-negative and 14 CIMP-positive clear cell RCCs and the corresponding non-cancerous renal cortex tissue specimens.
[Results] The number of genes showing genetic aberrations in CIMP-negative clear cell RCCs was quite low, indicating that CIMP-negative RCCs lacked distinct genetic characteristics. On the other hand, many genes, such as genes encoding hisotone modification enzymes and tumor-suppressor genes, showed 10% or more incidence of genetic aberrations in CIMP-positive clear cell RCCs. Based on MetaCore pathway analysis, although mRNA or protein expression alterations in CIMP-negative clear cell RCCs were not significantly accumulated in any molecular pathways, such alterations in CIMP-positive clear cell RCCs were accumulated in the 19 pathways (P&lt;0.05), such as molecular pathways involved in cell cycle and cell adhesion. Quantitative RT-PCR analysis verified expression alterations of genes involved in the most frequently affected pathway in CIMP-positive clear cell RCCs.
[Conclusion] The most frequently affected pathway may be a novel therapeutic target of CIMP-positive clear cell RCCs. We are now examining the effectiveness of the inhibitor of the most frequently affected pathway in RCC cell lines showing CIMP.
Citation Format: Eri Arai, Hiromi Sakamoto, Masaya Ono, Yoriko Takahashi, Sayaka Miyata, Hiroyuki Fujimoto, Masahiro Gotoh, Tesshi Yamada, Yae Kanai. Multilayer omics analyses in CpG island methylator phenotype clear cell renal cell carcinomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2316. doi:10.1158/1538-7445.AM2014-2316
Abstract 2330: Transcription factor MAZ promotes cell growth and aggressive behavior of human pancreatic cancer cells
Authors: Maity Gargi , Sarkar Sandipto , Dhar Kakali , Dhar Gopal , Haque Inamul , Banerjee Sushanta K. , Banerjee Snigdha 
Published: May 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cancer in the United States and the eighth worldwide. PDAC is most aggressive type of cancer that spreads rapidly and is seldom detected in its early stages as signs and symptoms may not appear until pancreatic cancer is quite advanced. MAZ (Myc-associated zinc-finger protein) or SAF1 (Serum amyloid A activating factor 1) gene is a member of multiple Cys2-His2-type zinc finger proteins that are activated in response to various inflammatory signals and may act as a transcription factor with dual roles in transcription initiation and termination. Deregulation of MAZ expression has been shown to be related to the development and progression of various cancers like prostate cancer, breast cancer and pancreatic cancer. However, mode of action of MAZ in carcinogenesis is unclear. We found that MAZ mRNA and protein levels were markedly elevated in pancreatic adenocarcinoma tissue samples as compared to adjacent normal tissues and the expression profile was increased as the disease progressed. Similarly, MAZ mRNA and protein levels were increased several folds in aggressive pancreatic cancer cell lines as compared to non-transformed pancreatic cancer cell lines. Functional analysis demonstrates that siRNA-based depletion of MAZ significantly inhibits in vitro cellular growth, colony formation, anchorage independent growth and invasion in pancreatic cancer cells. Mechanistically, MAZ regulates BIRC5, a pancreatic cancer promoting gene, to possibly exert its pathobiological function. Moreover, we found that CCN1/Cyr61 is an upstream regulator of MAZ. Collectively, these findings indicate that MAZ is a downstream target of CCN1 and plays an important role in pancreatic cancer progression and differentiation. Thus, MAZ could be an ideal target for PDAC management. [This work is supported by VA Merit Award Grant (SB/SKB)]
Citation Format: Gargi Maity, Sandipto Sarkar, Kakali Dhar, Gopal Dhar, Inamul Haque, Sushanta K. Banerjee, Snigdha Banerjee. Transcription factor MAZ promotes cell growth and aggressive behavior of human pancreatic cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2330. doi:10.1158/1538-7445.AM2014-2330
Abstract 2342: Related study on the fat mass and obesity associated FTO gene and melanoma
Authors: Niu Tianhui , Xiong Min , Tian Yan 
Published: May 2015

Abstract
FTO is a Fe(II)/2-oxoglutarate-dependent oxidative DNA/RNA demethylase and plays a key role in the fat metabolism and several chronic illnesses including cancer development. Several independent SNPs in the intron 8 of the FTO gene, showed nominally significant association with risk of melanoma. But the functional regulatory mechanism of FTO protein is poorly understood. Thus, the research of downstream factors and interaction proteins of FTO may identification of the mechanism FTO participated in and discovery of the FTO pathway may provide a noval evidence to the diagnosis and put forward new targets for the treatment of melanoma. Recent reports show that there is an important link between FTO and melanoma cancer. Our recent studies find that there are differences of FTO expression between normal skin and melanoma cancer. First of all, higher FTO protein expression was detected by western blot in melanoma cancer cells, compared with primary cultured normal skin cells. However, the mRNA expression of both normal tissue and melanoma cancer are at the similar level. Secondly, FTO expression was also investigated in 80 clinical samples. Compared with normal skin tissues, malignant melanoma tissues had stronger positive immunohistochemical (IHC) staining of FTO in nucleus, and IHC scoring confirmed the significantly higher FTO protein expression in carcinoma tissues. In the normal skin tissues, FTO only expressed in basal nuclei; but in the melanoma cancer, FTO expressed in the dermal cells both at the nucleus and membrane. Especially, the expression of FTO is closely related with the pathological staging of melanoma. The increased FTO expression in melanoma carcinoma suggested that aberrant FTO expression may be an early molecular event in cancer development. Simultaneously, we focus on identifying the specific regulation function of FTO in the melanoma cancer cell, using the cDNA microarray and Two-dimensional fluorescence difference gel electrophoresis combining with MALDI-TOF-MS technique to screen the interaction proteins and their mutual regulation, determine the molecules interaction with FTO in the melanoma cancer development. Taken together, these data demonstrated that there is an important link between FTO and melanoma cancer, FTO gene plays an important role in melanoma pathogenesis.
Note: This abstract was not presented at the meeting.
Citation Format: Tianhui Niu, Min Xiong, Yan Tian. Related study on the fat mass and obesity associated FTO gene and melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2342. doi:10.1158/1538-7445.AM2014-2342
Abstract 2344: 3D extracellular stiffness cues drive localized changes in gene expression
Authors: Bainer Russell , Yui Yoshihiro , Mumenthaler Shannon , Mallick Parag , Podlaha Ondrej , Michor Franziska , Liphardt Jan , Licht Jonathan , Weaver Valerie 
Published: May 2015

Abstract
The stiffness of the extracellular matrix (ECM) stimulates mechanotransduction pathways that regulate tissue development and tumor progression. We previously showed that a stiff ECM potentiates cell growth and survival, enhances cell migration to drive tumor cell invasion, and drives malignant progression of the mammary gland in culture and in vivo, but the specific transcriptional and molecular events that occur as cells acquire these phenotypic changes are not well understood. To clarify this process, we used expression microarrays, tandem mass spectrometry, and RNA sequencing to identify changes in gene expression levels, isoform usage, and protein abundance that occur as intact ascini respond to distinct stiffness environments. We found that in stiffer ECM conditions ascini acquire consistent changes in gene expression related to cell adhesion and mRNA splicing, and specifically induce the expression of a set of genes involved in epithelial cell differentiation that includes multiple SPRR and S100 proteins. Remarkably, these genes map to an apparent stiffness-mediated transcriptional hotspot on chromosome 1q21, a region containing elevated transcription in many cancers but whose activity has not been related to mechanotransduction. We then used a heuristic approach to identify additional candidate force-mediated transcriptional hotspots throughout the genome that contain multiple genes that are coordinately activated or silenced in response to elevated ECM stiffness. Provocatively, we find that genes whose expression levels are responsive to ECM stiffness cues are disproportionately located within chromosomal regions that associate with the nuclear lamina, suggesting that these transcriptional changes may be due in part to force-dependent alteration of genomic contacts with the nuclear envelope. These studies provide biological insight into the divergent cellular responses to distinct stiffness environments and suggest that genome regulatory responses to the force environment may specifically target distinct chromosomal regions via a mechanism that remains to be elucidated.
Citation Format: Russell Bainer, Yoshihiro Yui, Shannon Mumenthaler, Parag Mallick, Ondrej Podlaha, Franziska Michor, Jan Liphardt, Jonathan Licht, Valerie Weaver. 3D extracellular stiffness cues drive localized changes in gene expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2344. doi:10.1158/1538-7445.AM2014-2344