bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2291: Arsenic trioxide induces cell cycle arrest, apoptosis and MAPKinase signaling cascade in acute promyelocytic leukemia cells
Authors: Kumar Sanjay , Yedjou Clement , Tchounwou Paul B. 
Published: May 2015

Abstract
Arsenic trioxide (ATO) has recently been successfully used in the treatment of all-trans retinoic acid resistant relapsing acute promyelocytic leukemia (APL) patients both alone or combination with other drugs. Its use as induction and consolidation therapy has resulted in complete remission rate of both de novo and relapsed APL patients. However, the detailed molecular mechanisms of its therapeutic action are poorly known. We have used human leukemia (HL-60) cells as a model to elucidate the anti-cancer properties of arsenic trioxide. We hypothesized that ATO arrests cell cycle progression of HL-60 cells at G1 phase and leading to cell death by intrinsic pathway of apoptotic signaling. To test the hypothesis, we used western blotting, confocal imaging and spectrofluoremetric techniques to identify detailed cellular and molecular mechanisms of ATO action in HL-60 cells. We found that the expression levels of pro-apoptotic molecules (Bax) and cytochrome C were up-regulated, while that of anti-apoptotic Bcl2 protein was down-regulated at 4 and 6mg/mL ATO doses significantly. We also found that ATO stimulates signaling molecules like P38, JNK in a dose dependent manner in HL-60 cells. Oxidative stress and related imbalance of pro- and anti-apoptotic molecules lead to change of mitochondrial membrane potential and opening of the mitochondrial membrane transition pores. Our confocal imaging data shows a clear translocation of Bax from cytosol to mitochondria and of cytochrome c from mitochondria to cytosol in ATO-treated cells. A dose-dependent decrease/drop-down in mitochondrial membrane potential was also observed in ATO-treated cells, as evidenced by JC-1 leveling and spectrofluoremetric potential recording. On the basis of these findings, we conclude that mitochondrial pathway of apoptosis plays a key role in ATO pharmacology and should be further assessed as a drug target in APL chemotherapy.
Citation Format: Sanjay Kumar, Clement Yedjou, Paul B. Tchounwou. Arsenic trioxide induces cell cycle arrest, apoptosis and MAPKinase signaling cascade in acute promyelocytic leukemia 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 2291. doi:10.1158/1538-7445.AM2014-2291
Abstract 2300: Silencing of the transcription repressor HOXA2 by aberrant hypermethylation enhances invasion via MMP-9 activation in NPC
Authors: Peng Chen-Ching 
Published: May 2015

Abstract
Nasopharyngeal carcinoma (NPC) is notorious for its high invasiveness and metastatic ability. In this study, we identified a differential hypermethylated transcription repressor, Homeobox A2 (HOXA2), which may render NPC cells invasive and metastatic. Aberrant hypermethylation of HOXA2 led to low RNA expression in NPC tumors and cells. Addition of methylation inhibitor 5′Aza restored HOXA2 RNA expression in NPC cells. Methylated HOXA2 promoter reduces the binding affinity of the transcriptional co-activator p300, causing transcriptionalrepression of HOXA2. In NPC cells, re-expression of ectopic HOXA2 wascorrelated with decreased invasive ability and reduced metalloproteinase MMP-9 RNA and protein expression. Promoter, ChIP and DNA-pull down assays indicated that HOXA2 competes with the transcription activator, TATA-box binding protein (TBP) for a recognition sequence near the MMP-9 transcription start site, and suppresses MMP-9 transcription. Thus, HOXA2 acts as a suppressor or TBP-antagonist to inhibit MMP-9 expression; while methylation-mediated inactivation of HOXA2 in NPC derepresses MMP-9 production and increases invasion of NPC cells. In NPC plasma samples, increased plasma EBV copy number was correlated with increased in cell-free HOXA2 hypermethylation and elevated MMP-9 levels. Plasma EBV DNA and methylated cell-free HOXA2 can be used as biomarkers for monitoring NPC treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Chen-Ching Peng. Silencing of the transcription repressor HOXA2 by aberrant hypermethylation enhances invasion via MMP-9 activation in NPC. [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 2300. doi:10.1158/1538-7445.AM2014-2300
Abstract 2301: Cross validation of NGS methylated targets using droplet digital PCR (ddPCR)
Authors: Shelton Dawne N. , Litterst Claudia , Regan John F. , Moinova Helen R. , Markowitz Sanford D. 
Published: May 2015

Abstract
DNA methylation is one of the most studied epigenetic modifications. DNA methylation plays an important role in a number of physiological processes as well as common diseases such as cancer and neurodegenerative disorders. In mammals, DNA methylation occurs at the C-5 position of cytosine in CpG dinucle¬otide sequences, which are mainly concentrated in regions known as CpG islands. Methylation in CpG islands within gene promoters usually leads to gene silencing.
Recent data have shown the correlation of methylation and disease status. However, there are significant limitations in both biology and technology. Biologically, methylation status is highly heterogeneous in nature. In normal controls there is never a complete lack of methylation marks, and conversely, never a completely saturated methylation signature. In addition methylation sites of interest are often located in CpG islands, regions where multiple methylation sites occur side by side, making assay design and discrimination challenging. Technological hurdles add significant variability as well. The typical method for determining methylation is bisulfite conversion, which uses harsh chemicals to convert cytosines to uracil. When a cytosine is methylated, it is largely, though not completely, protected from the conversion process. However, bisulfite conversion also causes a great deal of DNA damage, causing the strands to separate and fragment. In most cases of research, the DNAs that researchers want to examine are from FFPE or cfDNA samples, samples which are already both limited and damaged.
Because of these challenges, there is an unmet need for a sensitive yet robust method to analyze DNA methylation in clinical samples in a rapid, inexpensive, and high throughput manner.
Herein we showcase the use of ddPCR for detection of DNA methylation in bisulfite converted gDNA samples. First we demonstrate the superior sensitivity, linearity and robustness of ddPCR methylation detection in the SNRPN promoter, a model system for an imprinted gene involved in neurological disorders. Secondly we show the detection of DNA methylation in the vimentin promoter, which is known to be methylated in cancer (Li et al. Nat. Biotech. 2009). We will demonstrate reproducible detection in replicate bisulfite converted samples and sensitivity.
Citation Format: Dawne N. Shelton, Claudia Litterst, John F. Regan, Helen R. Moinova, Sanford D. Markowitz. Cross validation of NGS methylated targets using droplet digital PCR (ddPCR). [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 2301. doi:10.1158/1538-7445.AM2014-2301
Abstract 2306: Pre-clinical development of 4′-thio-2′-deoxycytidine (TdCyd) as a DNA-demethylating agent for use in treating solid tissue tumors
Authors: Kinders Robert J. , Hollingshead Melinda , Thottassery Jaideep , Parker William B. , Pfister Thomas D. , Anderson Lawrence W. , Tomaszewski Joseph E. , Collins Jerry M. , Doroshow James H. 
Published: May 2015

Abstract
Targeting cancer epigenetic control of cell growth via DNA methylation has been successful in treating hematologic diseases, such as Decitabine (DAC) and Azacitidine for Myelodysplastic Syndrome including Acute Myelomonocytic Leukemia. This success has not extended to solid tissue tumors. The Division of Cancer Treatment and Diagnositcs of NCI has initiated pre-clinical development of TdCyd as an agent for treating solid tumors after promising early results in a lung adenocarcinoma xenograft model (NCI-H23). IP dosing at 5MKG (0.56 MTD) in nu/nu mice on a Q5D x 3 cycle schedule resulted in tumor stasis with no accompanying weight loss in the mice. A DAC-treated control arm treated at MTD resulted in tumor growth delay but not stasis, and a 10% weight loss was noted. Intratumoral levels of DNMT1 were reduced to undetectable levels in xenografts post administration of TdCyd by ELISA and Western Blot assays, but were unaffected by DAC treatment. Mass Spectrometry analysis demonstrated incorporation of both TdCyd and thiothymidine (TdThd) into H23 DNA. In vitro experiments on a selected panel of cancer cell lines confirmed the conversion of TdCyd to the triphosphate and re-expression of tumor suppressor proteins p15 and p16. Funded by NCI Contract No. HHSN261200800001E.
Citation Format: Robert J. Kinders, Melinda Hollingshead, Jaideep Thottassery, William B. Parker, Thomas D. Pfister, Lawrence W. Anderson, Joseph E. Tomaszewski, Jerry M. Collins, James H. Doroshow. Pre-clinical development of 4′-thio-2′-deoxycytidine (TdCyd) as a DNA-demethylating agent for use in treating solid tissue tumors. [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 2306. doi:10.1158/1538-7445.AM2014-2306
Abstract 2324: Phospho-MED1 mediates the transcriptional regulation of AR splice variants in castration-resistant prostate cancer
Authors: Liu Gang , Sprenger Cynthia , Wu Pin-Jou , Sun Shihua , Uo Takuma , Haugk Kathleen , Epilepsia Kathryn Soriano , Plymate Stephen 
Published: May 2015

Abstract
The appearance of constitutively active androgen receptor splice variants (AR-Vs) has been proposed as one of the causes of castration-resistant prostate cancer (CRPC). Prior to treatment with enzalutamide or abiraterone, around 20-30% of CRPC patients already have high levels of AR-Vs in their metastases, especially ARv567es, and this portends a rapid progression and shorter survival. However, the underlying mechanism of AR-Vs in CRPC transcriptional regulation still remains unclear. A distinct transcriptome enriched with cell cycle genes (like UBE2C) has been associated with AR-Vs, which indicates the possibility of a different transcriptional mechanism than that of wild type AR. In our study, we performed co-immunoprecipitation, ChIP and luciferase reporter assays to explore the components involved in ARv567es activated UBE2C transcription. We found that (i) MED1 is necessary for ARv567es induced UBE2C up-regulation and subsequent prostate cancer cell growth; (ii) p-MED1 is recruited to ARv567es independent of full-length AR; (iii) p-MED1 has higher recruitment to UBE2C promoter and enhancer regions in the presence of ARv567es, (iv) ARv567es enhanced UBE2C transcription could be blocked by silencing MED1; (v) ARv567es/p-MED1 signaling cross talks with the PI3K-AKT pathway but not the MAPK pathway, and (vi) FoxA1 and histone methylation are involved in ARv567es/p-MED1 induced UBE2C long range chromatin interactions. In summary, these data indicate that p-MED1 serves as a key mediator in ARv567es transcriptional regulation and suggests a mechanism by which AR-Vs promote the development and progression of CRPC.
Citation Format: Gang Liu, Cynthia Sprenger, Pin-Jou Wu, Shihua Sun, Takuma Uo, Kathleen Haugk, Kathryn Soriano Epilepsia, Stephen Plymate. Phospho-MED1 mediates the transcriptional regulation of AR splice variants in castration-resistant prostate cancer. [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 2324. doi:10.1158/1538-7445.AM2014-2324
Abstract 2327: Defining the determinants of sensitivity and resistance to BET bromodomain inhibition
Authors: Follmer Nicole , Mertz Jennifer , Conery Andrew , Bryant Barbara , Hatton Charlie , Centore Richard , Huang Hon-Ren , Spillane Kerry , Sims Robert 
Published: May 2015

Abstract
Selective inhibition of BET bromodomains by small molecule inhibitors has emerged as a promising therapeutic strategy for the treatment of cancer. Accordingly, we have recently initiated clinical trials to assess this mechanism in patients. Recent evidence demonstrates that BET bromodomain inhibition leads to anti-proliferative activity in pre-clinical models of hematological malignancies and solid tumors. This anti-proliferative activity involves down-regulation of the transcription factor MYC, among other cancer-relevant pathways. However, heterogeneity exists in the response to BET bromodomain inhibition at both the molecular and phenotypic level. Given this complexity, the molecular determinants of sensitivity and resistance to BET bromodomain inhibition remains poorly understood. Current efforts are aimed at addressing this key issue by integrating the following: (1) phenotypic endpoints observed upon BET bromodomain inhibition with transcriptional changes, including down-regulation of MYC and other transcription factors important for regulating proliferation and cell death, such as MYB and BCL-2,(2) transcriptional response with BET protein chromatin binding and eviction, and (3) phenotypic endpoints and transcriptional response with genomic context. Our data potentially stratify indications within hematologic malignancies and solid tumors, and provide insight into patient selection strategies.
Citation Format: Nicole Follmer, Jennifer Mertz, Andrew Conery, Barbara Bryant, Charlie Hatton, Richard Centore, Hon-Ren Huang, Kerry Spillane, Robert Sims. Defining the determinants of sensitivity and resistance to BET bromodomain inhibition. [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 2327. doi:10.1158/1538-7445.AM2014-2327
Abstract 2335: Thymoquinone induces the MUC4 mRNA-destabilizing activity of Tristetraprolin
Authors: Lee Hyun Hee , Lee Se-Ra , Leem Sun-Hee 
Published: May 2015

Abstract
Tristetraprolin (TTP) is an AU-rich element binding protein that destabilizes ARE-containing mRNAs. We previously reported that TTP suppresses several target genes such as those encoding proto-oncogenes and cytokines in various cancer cells. However, the signaling pathway to induce TTP expression is not well known. In this study, we investigate that Tymoquinone (TQ) which is an active ingredient derived from the medicinal plant Nigella satia induces the TTP mRNA and protein expression in AGS and MDA-MB231. TQ treatment destabilized a luciferase mRNA containing cIAP2, VEGF and MUC4 ARE. Transfected cells were treated with various kinds of MAPK inhibitors, treatment with Sorafenib (RAF inhibitor) and U0126 (MEK-1/2) reduced the TTP induction activity of TQ in a dose-dependent manner. We confirmed that co-treatment with sorafenib/U0126 and TQ also reduced TTP expression. Following TQ downregulated the expression of MUC4 in previous study, we next examined whether the changes of TTP expression affects the expression of MUC4. Overexpression of TTP decreased the stability of MUC4 mRNA and expression level of MUC4. On the contrary, inhibition of TTP using siRNA increased the MUC4 expression. MUC4 mRNA contains two AREs within the 3′UTR and TTP destabilized a luciferase mRNA containing MUC4 mRNA 3′UTR. Analyses of point mutants of MUC4 mRNA 3′UTR demonstrated that ARE2 were mostly responsible for the TTP mediated destabilization of MUC4 mRNA. Our data suggest that TQ enhances the mRNA and protein level of TTP via the modulation of the Raf-MEK MAPK signaling and suppressed cancer cell growth and promotion through destabilizing MUC4 mRNA as TTP novel target gene.
Citation Format: Hyun Hee Lee, Se-Ra Lee, Sun-Hee Leem. Thymoquinone induces the MUC4 mRNA-destabilizing activity of Tristetraprolin. [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 2335. doi:10.1158/1538-7445.AM2014-2335
Abstract 2336: Interplay of Fra-2/AP-1 and Ezh2/PRC2 orchestrates epidermal differentiation
Authors: Wurm Stefanie , Guinea-Viniegra Juan , Zhang Jisheng , Ezhkova Elena , Wagner Erwin Friedrich 
Published: May 2015

Abstract
Disrupted epidermal differentiation characterizes numerous inflammatory skin diseases and skin cancer that impact &gt;25% of the population. In search for a key mediator of differentiation, we identified Fra-2/AP-1 as a dominant regulator of terminal epidermal differentiation. Loss of Fra-2 in suprabasal keratinocytes was sufficient to give rise to epidermal differentiation defects, keratinocyte hyperproliferation as well as skin inflammation. Additionally, the epithelial-restricted, ectopic expression of Fra-2 in papilloma prone K5-SOS-F transgenic mice resulted in reduced tumor burden due to precocious differentiation.
Fra-2 transcriptionally controlled genes located within the Epidermal Differentiation Complex (EDC), encoding structural proteins, which form the skin barrier as well as keratinocyte derived chemokines. We found that Fra-2 induced EDC genes by binding to conserved AP-1 consensus sites in promoter regions. These consensus sites were also bound by the transcriptional repressor Ezh2. Besides binding to the same consensus sites, the methyl-transferase Ezh2 methylated Fra-2 on lysine residues in basal epithelial progenitor cells. Interestingly, the interaction of Fra-2 and Ezh2 was disrupted in the time course of keratinocyte differentiation, suggesting that the transcriptional activity of Fra-2 is modulated by Ezh2.
Collectively, we identify Fra-2 as an effector of terminal keratinocyte differentiation and uncover a distinct mechanism of how Ezh2 regulates epidermal differentiation by methylation of the transcription factor Fra-2.
Citation Format: Stefanie Wurm, Juan Guinea-Viniegra, Jisheng Zhang, Elena Ezhkova, Erwin Friedrich Wagner. Interplay of Fra-2/AP-1 and Ezh2/PRC2 orchestrates epidermal differentiation. [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 2336. doi:10.1158/1538-7445.AM2014-2336
Abstract 2339: Transcriptional basis for loss of cellular differentiation in colon cancer
Authors: Luk Ian Y. , Tran Hoanh , Tse Janson W. , Chueh Anderly C. , Chionh Fiona , Clemons Nicholas J. , Mariadason John M. 
Published: May 2015

Abstract
Background:
Colon cancer is a leading cause of cancer related death. Colon cancer arises due to uncontrolled cell proliferation, failure of cells to undergo apoptosis and loss of cellular differentiation. While the pathways which drive the uncontrolled proliferation of colon cancer cells are relatively well understood, the mechanistic basis for loss of cell differentiation is less well characterized. The aim of this study was to identify novel transcription factors that regulate the differentiation status of colon cancer cells.
Methods:
Affymetrix microarrays were used to identify transcription factors which are significantly differentially expressed between well differentiated and poorly differentiated colon cancer cell lines. Differential gene expression was confirmed by q-RT-PCR in 40 colon cancer cell lines. The well differentiated colon cancer cell line SW948 was transfected with siRNAs using lipofectamine.
Results:
Microarray analysis of well and poorly differentiated colon cancer cell lines identified the EHF transcription factor to be significantly downregulated in expression in poorly differentiated cell lines. Q-RT-PCR analysis demonstrated that while both EHF variants were expressed in a panel of 40 colon cancer cells, variant 2 was the isoform differentially expressed between well and poorly differentiated cell lines. Basal expression of EHF correlated significantly with expression of the differentiation markers villin and KRT20 across the 40 cell line panel. Knockdown of EHF in the well differentiated colon cancer cell line SW948, reduced expression of villin and KRT20 by 82% and 64% respectively. Knockdown of EHF also reduces expression of Cdx1 suggesting it may be act upstream of this known differentiation regulator.
Conclusion:
This study identifies the transcription factor EHF as a novel regulator of cell differentiation in colon cancer.
Citation Format: Ian Y. Luk, Hoanh Tran, Janson WT Tse, Anderly C. Chueh, Fiona Chionh, Nicholas J. Clemons, John M. Mariadason. Transcriptional basis for loss of cellular differentiation in colon cancer. [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 2339. doi:10.1158/1538-7445.AM2014-2339
Abstract 2340: Disentangling the Myc:Max from the Mad:Max network
Authors: Rebocho Ana Paula , Littlewood Trevor , Evan Gerard I. 
Published: May 2015

Abstract
The Myc family comprises three basic helix loop helix leucine zipper (bHLHLZ) transcription factors - C-myc, N-myc and L-myc - which regulate a plethora of intra and extracellular processes. Myc, when bound to Max, another bHLHLZ transcription factor, is able to bind specific DNA sequences, recruit coactivator complexes and promote transcriptional activation. Max can also promote transcriptional repression by dimerizing with distinct transcription factors such as Mad. Previous work has shown that Myc expression promotes proliferation whereas Mad expression leads to differentiation, implying that Myc and Mad have opposing roles in cells. Myc and Mad share the same heterodimeric partner, Max, suggesting that the cell proliferation/differentiation fate is determined by a Myc:Max:Mad network. To understand how this equilibrium is maintained, we are investigating the effects of separating the Myc:Max from the Mad:Max network. To separate these networks we have made use of specific Myc and Max mutant proteins in which reciprocal exchanges at the e and g positions of the leucine zipper have been introduced. Whereas the MycEG and MaxEG proteins dimerize with each other they are unable to associate with their wild type counterparts. Using these mutants we will determine whether cell fate is dictated by a balanced Myc:Max:Mad network or whether Max is simply a common binding partner for both Myc and Mad. In order to validate the EG mutants in vitro, we have used mouse embryonic fibroblasts derived from a c-Myc ER/ER mouse model generated in our laboratory, in which ER is fused to endogenous c-terminus, allowing Myc to be toggled on and off at will. These cells have to be cultured in the presence of the ER ligand, 4-hydroxytamoxifen (4OHT), so that C-myc is functional and the cells proliferate normally. Whereas MycEG or MaxEG alone are unable to support growth of these cells in the absence of 4OHT, the proliferative arrest phenotype observed without 4OHT is rescued by co-expression of MycEG and MaxEG. We are currently generating mouse models where C-mycEG and MaxEG will replace the endogenous proteins in order to separate the roles of Myc:Max and Mad:Max in development and adult tissues.
Citation Format: Ana Paula Rebocho, Trevor Littlewood, Gerard I. Evan. Disentangling the Myc:Max from the Mad:Max network. [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 2340. doi:10.1158/1538-7445.AM2014-2340