bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3016: Roles of histone deacetylase inhibitors in the regulation of DNA methyltransferase 1
Authors: Takashima Asami , Faller Douglas V. 
Published: June 2012

Abstract
DNA methylation and histone deacetylation are the two major classes of genomic modifications which can contribute to transcriptionally-repressive chromatin structure.Tumor suppressor genes are hypermethylated in their promoter regions in certain cancers, which leads to transcriptional repression of these genes, and histone deacetylases (HDACs) cooperate with DNA methyltransferases (DNMTs) in this process, by their subsequent recruitment to methylated DNA. HDAC inhibitors, which can variably induce differentiation, apoptosis and/or cell cycle arrest in tumor cells, are known to alter gene expression patterns by disrupting the transcriptional regulatory complexes with which DNMT1 and HDAC1 or HDAC2 associate. Surprisingly, a series of recent studies by our group and others, using HDAC inhibitors, suggests that HDAC activity may influence DNA methylation, in addition to the established and reciprocal ability of CpG methylation to influence HDAC recruitment and transcriptional repression. HDAC inhibitors appear to influence DNA methylation by regulating the expression of DNMT1, although the molecular pathway mediating this regulation has not been fully elucidated. We have documented DNMT1 downregulation at the level of mRNA and protein abundance in human cancer cell lines, following exposure to any of several structurally-different HDAC inhibitors, suggesting that HDAC inhibitors decrease DNMT1 expression at the level of mRNA. We determined at which level, transcription or RNA degradation, DNMT1 mRNA is affected by HDAC inhibition, by measuring the time course of RNA degradation using real-time PCR following treatment of Actinomycin D, an inhibitor of de novo transcription. In spite of their ability to upregulate AUF1, a known regulator of DNMT1 mRNA stability, HDAC inhibitors did not significantly alter DNMT1 mRNA half-life in comparison to vehicle-treated controls. In agreement with this finding, specific knockdown of AUF1 by siRNA did not abrogate the decrease in DNMT1 protein expression caused by HDAC inhibition. Exposure to HDAC inhibitors in the presence of cycloheximide, an inhibitor of de novo protein synthesis, prevented the downregulation of DNMT1 mRNA, suggesting that new protein synthesis is required for the effect of HDAC inhibitors on DNMT1 expression. Thus, the downregulation of DNMT1 expression by HDAC inhibitor treatment is induced at the transcriptional level in LNCap cells, possibly in an indirect manner. These findings begin to elucidate the mechanism whereby HDACs and their inhibitors may influence DNA methylation, in addition to the established and reciprocal ability of CpG methylation to influence HDAC recruitment and transcriptional repression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3016. doi:10.1158/1538-7445.AM2011-3016
Abstract 3019: Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells
Authors: Cho Hyun-Soo , Nakamura Yusuke , Hamamoto Ryuji 
Published: June 2012

Abstract
Histone demethylase LSD1 (also known as KDM1 and AOF2) is active in various cancer cells, but its biological significance in human carcinogenesis is unexplored. In this study, we explored hypothesized interactions between LSD1 and MYPT1, a known regulator of RB1 phosphorylation. We found that MYPT1 was methylated in vitro and in vivo by histone lysine methyltransferase SETD7 and demethylated by LSD1, identifying Lys 442 of MYPT1 as a target for methylation/demethylation by these enzymes. LSD1 silencing increased MYPT1 protein levels, decreasing the steady-state level of phosphorylated RB1 (Ser 807/811) and reducing E2F activity. MYPT1 methylation status influenced the affinity of MYPT1 for the ubiquitin-proteasome pathway of protein turnover. MYPT1 was unstable in murine cells deficient in SETD7, supporting the concept that MYPT1 protein stability is physiologically regulated by methylation status. LSD1 overexpression could activate RB1 phosphorylation by inducing a destabilization of MYPT1 protein. Taken together, our results comprise a novel cell cycle regulatory mechanism mediated by methylation/demethylation dynamics, and they reveal the significance of LSD1 overexpression in human carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3019. doi:10.1158/1538-7445.AM2011-3019
Abstract 3020: Transcriptional repressive H3K9 and H3K27 methylations are essential for DNMT1-mediated DNA methylation recovery
Authors: Wong Chun-Ming , Ng Irene Oi-Lin 
Published: June 2012

Abstract
DNA methylation and histone modifications are two major epigenetic events regulating gene expression and chromatin structure, and their alterations are linked to human carcinogenesis. DNA methylation plays an important role in tumor suppressor gene inactivation, and can be revised by DNA methylation inhibitors. The reversible nature of DNA methylation forms the basis of epigenetic cancer therapy. However, it has been reported that DNA re-methylation and gene re-silencing could occur after removal of demethylation treatment and this may significantly hamper the therapeutic value of DNA methylation inhibitors. In this study we have provided detailed evidence demonstrating that mammalian cells possess a bona fide DNA methylation recovery system. We have also shown that DNA methylation recovery was mediated by the major human DNA methyltransferase, DNMT1. Moreover, the DNA methylation recovery function of DNMT1 was cell division-independent and likely to be distinct from its conventional “maintenance” DNA methyltransferase function. In addition, we found that H3K9-tri-methylation and H3K27-tri-methylation were closely associated with this DNA methylation recovery. These persistent transcriptional repressive histone modifications may have a crucial role in regulating DNMT1-mediated DNA methylation recovery. Our findings may have important implications towards a better understanding of epigenetic regulation and future development of epigenetic therapeutic intervention.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3020. doi:10.1158/1538-7445.AM2011-3020
Abstract 3043: FXR1 promotes lung cancer cell growth by regulating oncogenic targets in the 3q26-3q28 amplicon
Authors: Qian Jun , Zou Yong , Rahman Jamshedur , Hassanein Mohamed , Massion Pierre 
Published: June 2012

Abstract
Gain of chromosome 3q26-28 is one of the most common genomic imbalances in non-small cell lung cancer (NSCLC), particularly in squamous cell carcinomas (SCC). A comprehensive approach combining array CGH, mircroarray expression and shotgun proteomics data analysis reveals amplification, overexrpession of a candidate gene on 3q26, fragile-X-mental-retardation-related protein 1 (FXR1) in lung cancer. FXR1 is amplified and overexpressed in NSCLC tumors and highly correlated with several 3q26-28 targets including epithelial cell transforming sequence 2 (ECT2), protein kinase C iota (PKCi) and eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) measured by Real time-PCR and immunohistochemistry. We hypothesized that FXR1 is associated with these oncogenes and plays a critical role in lung cancer progression. ECT2 is known to promote lung cancer by binding to PKCi and activating MAPK signaling pathway. We found that overexpressing FXR1 in an immortalized human bronchial epithelial cell line (HBEC3KT) leads to upregulated expression of ECT2, PKCi and ERK1/2 activity. Downregulation of FXR1 using siRNA in lung cancer cell lines H520 and HCC95 induces the decreased expression of ECT2, PKCi and EIF4G1. Immunoprecipitation confirms that FXR1 binds to PKCi and EIF4G1 in NSCLC cells. Loss of FXR1 using siRNA treatment inhibits cell growth and survival of NSCLC cells that harbor 3q26-28 amplicon. Our results demonstrate the oncogenic potential of FXR1 and supports the concept that amplified targets on 3q26-28 are genetically and functionally associated to drive lung cancer cell growth.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3043. doi:10.1158/1538-7445.AM2011-3043
Abstract 3045: Dual functions of NDRG1 in cell growth and invasion
Authors: Li Hsiao-Fang , Cheng Ann-Joy 
Published: June 2012

Abstract
Head neck cancer (HNC) is a top ten leading cancers in Taiwan. Since this cancer usually occurs in the middle age male, at the high peak of life responsibility, it has tremendous impact of family and society. Previously through differential display analysis, we have identified several genes associated with HNC including NDRG1 (N-myc downstream-regulated gene-1), which is over-expression in HNC. In the present study, we further investigate cellular function of this gene leads to cancer development. NDRG1 expression was modulated by shRNA and full-length plasmid transfection and the potential alterations of cellular phenotypes were examined. Results showed that NDRG1 suppressed cell growths by 14% to 55%. This phenomenon was confirmed by colony formation. However, by using wound healing assay the cell migration increased (17% ∼ 43%) and by using matrigel invasion assay the invasion increased (7 ∼ 12 folds). Both migration and invasion were significantly enhanced. These results suggest that NDRG1 plays dual functions in tumorigenesis with multiple aspects
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3045. doi:10.1158/1538-7445.AM2011-3045
Abstract 305: EphB4 and EphrinB2 regulates ovarian cancer progression
Authors: Tan Wei , Yang Suijin , Looper David , Nowlin Dawn , Huang Zhongdong , Los Gerrit , Jani Jitesh P. 
Published: June 2012

Abstract
EphB4 belongs to the Eph Receptor Tyrosine Kinase family. EphB4 regulates angiogenesis, neuron migration and breast morphogenesis. Overexpression of EphB4 has been observed in numerous cancer types, including breast, ovarian and prostate cancers. How EphB4 regulates cancer progression is still largely unknown. EphrinB2 is the unique ligand for EphB4. EphrinB2 triggers phosphorylation, activation and down-regulation of EphB4. We analyzed various ovarian cancer cell lines and patient derived xenograft samples by in vitro and in vivo assays including siRNA knockdown and gene expression profiling. A large portion of ovarian cancer models express both EphB4 and ephrinB2. SiRNA targeting of EphB4 induced growth inhibition and induction of apoptosis in several cell lines. Serous ovarian carcinoma cell line, Ovcar-3 which expresses both EphB4 and ephrinB2 was most sensitive to siRNA targeting. Non ephrinB2 expressing cell lines were less sensitive suggesting that sensitivity to EphB4 siRNA targeting is not only dependent on the levels of EphB4 but also the status of ephrinB2. Gene expression profiling studies showed that EphB4 is implicated in signaling transduction, cell attachment and growth. Currently, we are examining how ephrinB2 expression modulates EphB4 signaling and the down-stream effectors of EphB4 signaling pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 305. doi:10.1158/1538-7445.AM2011-305
Abstract 3051: The vitamin D2 analog 19-nor-1,25-dihydroxyvitamin D2: antitumor activity against gastric cancer cells
Authors: Bae Woo Kyun , Park Myung Suk , Lee Ji Hee , Hwang Jun Eul , Yoon Joo Young , Shim Hyun Jeong , Cho Sang Hee , Lee Jae Hyuk , Chung Ik Joo 
Published: June 2012

Abstract
Background: The active metabolite of vitamin D, 1, 25-dihydroxyvitamin D3 (calcitriol), inhibits the growth of several types of human cancer cells in vitro, but its therapeutic use is limited because it causes hypercalcemia. Among its analogs, 19-nor-1, 25-dihydroxyvitamin D2 (paricalcitol) induces fewer calcemic effects and exhibits an activity that is equipotential to that of calcitriol in several in vivo and in vitro systems. We investigated the antitumor activity and mechanism of action of paricalcitol in gastric cancer cells.
Methods: We examined the effects of paricalcitol on cell proliferation, cell cycle, apoptosis, and inflammation/immunity in the human gastric cancer cell lines AGS, SNU719, and MKN45.
Results: In vitro treatment with paricalcitol was associated with the following: (1) a dose-dependent increase in vitamin D receptor (VDR) protein expression; (2) inhibited gastric cell growth and induced apoptosis in AGS, SNU719, and MKN45 cell lines; (3) increased expression of p21 and p27 and decreased expression of CDK2; (4) increased expression of the caspase-3 cleaved protein and decreased expression of the anti-apoptotic Bcl-2 and Bax proteins; (5) promotion of early and late apoptosis; and (6) decreased expression of STAT-3, JAK2, COX2, and NF-κB.
Conclusion: The low-calcemic vitamin D analog, paricalcitol, exhibits anticancer activity against gastric cancer cells, and its mechanism of action may be mediated through the VDR. Paricalcitol is a promising agent for the prevention and treatment of gastric cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3051. doi:10.1158/1538-7445.AM2011-3051
Abstract 3056: Amplification of the BP1 homeobox gene in familial breast cancer with BRCA1/2 mutations
Authors: Pereira Silma R. , Oliveira Marcia M.C. , Haddad Bassem R. , Berg Patricia E. , Cavalli Luciane R. 
Published: June 2012

Abstract
Background: BP1 is a homeobox gene which was reported to be amplified and overexpressed in breast tumors with poor clinical outcome. Its exact role and function in breast tumorigenesis is not known and no studies have investigated its role in familial breast cancer cases. BP1 is located on 17q21, a chromosomal region that is altered in a high percentage of breast tumors; CGH analysis of the 17q region demonstrated gains in 50% and 85% of BRCA1 and BRCA2 mutated familial breast tumors, respectively. BP1 has been found to be overexpressed in breast cancer cells defective in double-strand break repair by homologous recombination (BRCA defective) and has been shown to directly regulate BRCA1 expression. The above information formed our rationale to evaluate the amplification of BP1 in familial breast cancer patients with known BRCA1/2 mutation status. We hypothesized that BP1 would be preferentially amplified in BRCA1/2 mutations carriers and correlated with poor clinical prognostic factors.
Methods: Three tissue microarrays, containing tumor tissues of a total of 67 familial breast cancer patients, with known BRCA1/2, ER and PR status and full clinical data, were obtained from the Familial Cancer Registry from Georgetown University. FISH analysis was performed using a specific BP1 FISH probe developed in our lab.
Results: FISH scoring in 100 cells was performed in 87% of the patients. Amplification of BP1 was observed in 26% of the cases and was significantly correlated with the presence of mutations in the BRCA1/2 genes, as opposed to patients with full negative (FN), Jewish panel negative (JPN) and variant with unknown significance (VUS). BP1 amplification was also significantly correlated with large tumor size (&gt;1.5cm) and poorly differentiated tumors. Upon stratification of the samples by histological type, a total of 173 lesions (from cores containing different lesions from the same patients) were analyzed. Similar frequencies of BP1 amplification were observed in invasive (24%) and ductal carcinoma in situ (23.6%) lesions.
Conclusions: Our findings demonstrate that the BP1 homeobox gene is amplified in familial breast cancer patients and its amplification is correlated with the presence of mutations in the BRCA1/2 genes as well as poor clinical prognostic factors, such as large tumor size and poorly differentiated tumors. Studies evaluating the expression of BRCA1 and BP1 proteins in these samples are in progress, in order to identify possible mechanism of interactions and related pathways between BP1 positive and BRCA1 mutant tumors in familial breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3056. doi:10.1158/1538-7445.AM2011-3056
Abstract 3057: Identification and characterization of SPOCK1 in HCC development
Authors: Li Yan , Chan Hon Man , Chen Leilei , Guan Xin-Yuan 
Published: June 2012

Abstract
EIF5A2 is a recently identified oncogene in HCC which can enhance cell motility and promote tumor metastasis. To explore its oncogenic mechanisms, an mRNAs profiling microarray was carried out to identify downstream targets. Among the genes differentially regulated by EIF5A2, SPOCK1 was further investigated. The protein encoded by SPOCK1 is a component of the extracellular matrix, which is predicted to be involved in cell adhesion and migration. Overexpression of SPOCK1 was detected in approximately 70% of human HCC samples analyzed and positively correlated with EIF5A2 expression. Functional studies found that ectopic expression of SPOCK1 could promote cell proliferation, anchorage-dependent growth, anchorage-independent growth and invasion in HCC cells. In vivo, SPOCK1 over-expressed stable clones formed bigger tumors when compared to controls. Silencing SPOCK1 expression by shot-hairpin knock-down approach effectively abolished the tumorigenic and metastatic abilities of HCC cell line.
Furthermore, as detected by the functional studies, over-expression of SPOCK1 increased MMP9 level in HCC cells. Western blotting analysis revealed an increase of sheared fibronectin as the result of full-length fibronectin degradation. As SPOCK1 belongs to a matricellular glycoprotein family that mediates interactions between cells and their microenvironment, the above results suggest it may promote invasion by regulating matrix deposition and turnover.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3057. doi:10.1158/1538-7445.AM2011-3057
Abstract 3062: A comparative analysis of phosphothioated DNA and peptide nucleic acid molecular beacons targeting specific K-ras mutation
Authors: Kam Yossi , Rubinstein Abraham , Nissan Aviram , Halle David , Yavin Eylon 
Published: June 2012

Abstract
Introduction: Early detection of gastrointestinal malignancies may improve disease-related outcome. In vivo, real time imaging using hybridization of fluorescently-labeled complementary transcripts to intracellular RNA sequences may facilitate early detection of malignant and pre-malignant lesions
Methods: Using K-ras oncogene as a model target, and adapting the molecular beacon technology, we performed an hybridization kinetics and hybridization specificity comparison of two types of molecular beacons (MBs) based on either phosphothioated DNA (PS-DNA-MB) or peptide nucleic acid (PNA-TO-MB, where thiazole orange [TO] was used as the fluorescent molecule) both in vitro and in a variety of cell lines. In order to determine the sequence-specificity of MB's at a single base resolution, a codon 12 K-ras oncogene mutation (GGT→GAT) was used as target in different cell lines. Both PS-DNA and PNA-TO MB's were designed to target this specific K-ras point mutation. We studied the hybridization of the two MBs to wild-type K-ras (HT-29 colon cancer cell line) and two cell lines, one harboring this K-ras point mutation (PANC-1) and SW-480 harboring a different (GGT→GTT) mutation.
Results: Hybridization kinetics of PNA-TO-MB to target DNA or RNA was faster compared to PS-DNA-MB highlighting the advantage of such probes to be developed into diagnostic kits for the early detection of cancer. However, in solution, using synthetic DNA oligomers as targets, PS-DNA-MB demonstrated higher specificity to its complementary target (3-to 4.6-fold increase in fluorescence in comparison to DNA with a single mismatch) compared to the PNA-TO-MB (only 1.3- to 2.2-fold increase). Yet, incubation of PNA-TO-MB with total RNA (isolated from these cell lines) and with fixed cells, resulted in a significantly higher fluorescent signal (p &lt; 0.001) detected for target (fully complement, PANC-1) compared to single mismatch mRNA transcript in HT29 and SW-480. In contrast, the PS-DNA-MB showed poor discrimination in total RNA and no fluorescent signal with all cell lines after 5 minutes incubation.
Conclusions: Based on the fast hybridization kinetics and based on the single mismatch discrimination found for PNA-TO-MB in fixed cells and with total RNA, it is speculated that such PNA-TO-MB's are promising candidates for the early detection of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3062. doi:10.1158/1538-7445.AM2011-3062