bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A21: Orphan nuclear receptor TLX recruits lysine-specific demethylase 1 to repress androgen receptor gene transcription and functions to promote hormone-resistant growth of prostate cancer cells
Authors: Jia Lin , Wu Dinglan , Yu Shan , Chan Franky Leung 
Published: August 2014

Abstract
Prostate cancer (PCa) is the most frequently diagnosed type of cancer and the second leading cause of death from cancer in males in the United States. The initial growth of most localized PCa is slow and androgen-dependent. Thus, surgical treatment (prostatectomy) and hormone therapy (androgen deprivation) are effective initially. However, many patients relapse and progress to a fatal androgen-independent and bone-metastatic stage shortly when both primary and secondary hormone therapies fail. Unfortunately, the current options for the metastatic hormone-refractory PCa are still limited and mostly ineffective, resulting in high mortality of this disease. Although dysregulated androgen receptor (AR) signaling pathway has been proposed to contribute to the development of hormone-resistance, the involved mechanisms are still not fully defined. Our present findings revealed that the orphan nuclear receptor TLX (NR2E1) exhibited increased expression patterns in androgen-independent and antiandrogen-resistant PCa cells, and also the high-grade and hormone-refractory clinical PCa tissues. Stable overexpression of TLX in AR-positive LNCaP cells could promote both androgen-independent and antiandrogen-resistant cell growth in vitro, and enhance tumor growth capacity in castrated male SCID mice in vivo. Decreased expression of AR and AR target genes in LNCaP-TLX cells were identified, while results of AR-promoter driven luciferase reporter assay also revealed that TLX overexpression could suppress the AR transcription in non-prostatic HEK293 cells. Furthermore, we also identified the direct binding site of TLX on the AR promoter by chromatin immunoprecipitation analyses in TLX-transfected HEK293 cells. The molecular mechanism may involve the TLX-mediated recruitment of lysine-specific demethylase 1 (LSD1) as treatment with an inhibitor of LSD1 pargyline could reverse the transrepressive regulation of TLX on AR-promoter driven luciferase activity and restore AR gene expression levels in LNCaP cells. In summary, our results showed for the first time that overexpression of TLX might contribute to the hormone-resistant PCa cell growth and advanced progression of PCa. LSD1 might serve as a corepressor in TLX-mediated direct transrepression on AR gene expression.
This work is partly supported by an RGC-General Research Fund CUHK461012.
Citation Format: Lin Jia, Dinglan Wu, Shan Yu, Franky Leung Chan. Orphan nuclear receptor TLX recruits lysine-specific demethylase 1 to repress androgen receptor gene transcription and functions to promote hormone-resistant growth of prostate cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A21.
Abstract A45: Chromatin dynamics of the zebrafish retina during development and aging
Authors: Wei Xiangyun 
Published: August 2014

Abstract
During organogenesis, the retina develops from a single sheet of undifferentiated neuroepithelium into a layered mature tissue composed of Müller, photoreceptor, horizontal, bipolar, amacrine, interplexiform and ganglion cells. This differentiation of various retinal cell types requires the transcription of distinct sets of genes in precise temporal orders. It is unclear how chromatin organization and modifications are specifically regulated at global and regional levels to facilitate the generation of distinct transcriptional profiles required for different retinal cell types. Nor do we know to what extent chromatin structure and organization are altered during retinal aging, or how such alterations lead to unbalanced gene expression profiling and subsequent cell degeneration. In this study, we analyzed the dynamic characteristics of nuclear structures and chromatin organizations of zebrafish retinal cells during development and aging. We show that the degrees of chromatin condensation vary significantly among different retinal cell types, as suggested by varying nuclear volumes and heterochromatin/euchromatin organization. These structural features are altered during the aging process as well. For example, the nuclear volumes of cone photoreceptors increase significantly during aging. The distribution patterns of H3K9me3 and H4K20me3 heterochromatin modifications also vary dramatically among different retinal cell types and at different ages. The gross alterations in nuclear structures and chromatin condensation may suggest extensive changes in gene expression activities. These findings provide insight into how chromatin organization and modifications underlie balanced global transcriptional profiles and consequently, the overall fitness of retinal cells, as well as how such regulations might be altered during the aging process. Our study may have significant social impact because with increasing life expectancy, more and more older people will suffer from age-related macular degeneration and the identification of proper interventions to slow down the retinal aging process would dramatically enhance quality of the life for the elderly.
Citation Format: Xiangyun Wei. Chromatin dynamics of the zebrafish retina during development and aging. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A45.
Abstract A57: Dual role of the histone methyltransferase PR-SET7/SETD8 in the local regulation of Pol II promoter-proximal pausing
Authors: Kapoor Priya , Vertino Paula M. 
Published: August 2014

Abstract
Tumor suppressor gene silencing in cancers is often achieved through epigenetic mechanisms which involve the hypermethylation of promoter-associated CpG islands and a local shift from permissive to repressive histone modifications. Recently, we showed that epigenetic silencing of the tumor suppressor gene TMS1/ASC in human breast cancer cells is accompanied by a local shift from histone H4 lysine 16 acetylation (H4K16Ac) to H4 lysine 20 trimethylation (H4K20me3). H4K16Ac and H4K20me3 were found to play antagonistic roles in the regulation of RNA polymerase II promoter-proximal pausing, a critical post-initiation regulatory step that controls the rate of release of initiated Pol II into productive elongation and ultimately transcriptional output. We found that H4K16Ac, mediated by the histone acetyltransferase hMOF and acting in the MSL complex, facilitates the release of paused Pol II by promoting the recruitment of the BRD4/pTEFb complex whereas the local deposition of H4K20me3, mediated by the histone methyltransferase SUV420H2, enforces the pause and promotes gene repression by inhibiting the recruitment of MSL and subsequent H4K16Ac. However, how the local balance between hMOF-mediated H4K16Ac and SUV420H2-mediated H4K20me3 is achieved and converge to regulate Pol II pausing remains unclear. Here, we demonstrate that the histone methyltransferase PR-SET7/SETD8, which monomethylates histone H4 lysine 20 (H4K20me1), controls both H4K16Ac and H4K20me3, and as a result, regulates Pol II pausing and release. Specifically, we show that PR-SET7 and/or H4K20me1 is necessary for the local recruitment of the MSL complex, subsequent H4K16Ac and release from pausing. Although dispensable for SUV420H2 recruitment, PR-SET7 is required for SUV420H2-mediated H4K20me3, playing a role in enforcing Pol II pausing and subsequent epigenetic gene silencing. Whereas depletion of SUV420H2 is sufficient to deplete H4K20me3 and relieve H4K20me3-mediated Pol II pausing, pausing is maintained in the absence of PR-SET7 and local H4K20me1 due to a failure to recruit the MSL complex. These findings highlight the requirement for PR-SET7 and H4K20me1 in establishing both the H4K16Ac and H4K20me3 marks and points to its dual role in the regulation of Pol II pausing dynamics. Furthermore, our data suggests that the reversible repression imposed by the local conversion of H4K20me1 to H4K20me3 is a critical intermediate step in the epigenetic silencing of tumor suppressor genes in cancers.
Citation Format: Priya Kapoor, Paula M. Vertino. Dual role of the histone methyltransferase PR-SET7/SETD8 in the local regulation of Pol II promoter-proximal pausing. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A57.
Abstract A60: Analysis of gene copy number changes in chronic lymphocytic leukemia
Authors: Dalay Nejat , Isin Mustafa , Cetin Guven , Aktan Melih 
Published: August 2014

Abstract
Chronic lymphocytic leukemia (CLL) is the most frequent type of leukemia in the elderly and is accompanied by the accumulation of malignant monoclonal B-cells in the bone marrow, peripheral blood or lymph nodes which harbor various genetic aberrations. Genomic instability is an important characteristic of leukemia cells and plays a role both in its development as well as in the response to therapy. Somatic copy number changes in distinct genes are associated with the development of specific leukemias. Copy number variations are important diagnostic tools and help in classifying the disease and guiding the therapy. Current strategies for the detection of chromosomal aberrations in CLL are laborious and time consuming. Using multiplex ligation dependent probe amplification (MLPA) copy number changes at multiple loci can be detected simultaneously in a single simple PCR reaction. In this study, we investigated the copy number alterations in several key genes in CLL by MLPA.
DNA was isolated from the venous blood samples from 92 patients with CLL and 10 healthy controls. Copy number changes of 20 genes were analyzed at 29 different sites by MLPA. DNA samples were hybridized with the sequence specific probes for each gene and the hybridized probe pairs were ligated. PCR reaction was performed to amplify the ligated probes. PCR products were separated by capillary electrophoresis using the ABI Prism 310 genetic analyzer. The peaks were evaluated for the genomic gains and losses after normalization of each peak. Reference genes were used for normalization of each gene signal. The data from the patients were compared with control samples from healthy individuals.
Various genetic aberrations were detected in the patients with CLL. The most frequently observed genetic aberrations were losses in the chromosomal regions 13q14.3 and 13q14.2 and involved the DLEU7 (49 %), DLEU2 (41 %), KCNRG (35.9 %) and RB1 (14 %) genes. Copy number losses in the MYCN, ESR1, EIF3S3, CDKN2A, CDKN2B, ATM, CHFR and TP53 genes were lower with a frequency ranging between 1-10 %.
The most frequently amplified gene was the MYC gene (30.4 %), followed by the LRMP (17.4 %), ESR1 (15 %) and CHFR (14 %) genes. Gains in the MYCN, IGF2R, PARK2, CCND2, CDK4, IFNG and LDLR genes were observed with a lower frequency.
Our data indicate that copy number changes in several important genes are frequent in the pathogenesis of CLL. Simultaneous analysis and characterization of these genetic alterations can be performed using MLPA and the test can provide valuable clinical information when employed as a first-line screening approach for CLL patients.
Citation Format: Nejat Dalay, Mustafa Isin, Guven Cetin, Melih Aktan. Analysis of gene copy number changes in chronic lymphocytic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A60.
Abstract B02: Telomere-driven chromosome instability impacts on microRNA expression through epigenetic mechanisms
Authors: Jouravleva Karina , Castro-Vega Luis , Londono-Vallejo Arturo 
Published: August 2014

Abstract
Telomere shortening is a major source of chromosome instability (CIN) at early stages during carcinogenesis. However, the mechanisms through which telomere-driven CIN (T-CIN) contributes to the acquisition of tumor phenotypes remain uncharacterized.
We have used human epithelial kidney cells (HEK cells), a well-established in vitro model of progressive telomere instability, to study the impact of T-CIN in the expression of miRs and the biological consequences that might be relevant for the acquisition of tumor phenotypes.
We discovered that human epithelial kidney cells undergoing T-CIN display massive microRNA (miR) expression changes that are not related to local losses or gains. This widespread miR deregulation encompasses a miR-200-dependent epithelial-to-mesenchymal transition (EMT) that confers to immortalized pretumoral cells phenotypic traits of metastatic potential. Since deregulation of miRs in HEK CIN+ cells was widespread, orchestrated, and not related with copy number changes we hypothesized that this phenomenon utilizes epigenetic cues. Indeed, investigation of the mechanisms controlling miR-200 expression revealed that both DNA methylation and histone modifications changed significantly in cells undergoing T-CIN. Unbiased approaches are now being used to describe the epigenome changes genome-wide that are associated with CIN during cell transformation.
Citation Format: Karina Jouravleva, Luis Castro-Vega, Arturo Londono-Vallejo. Telomere-driven chromosome instability impacts on microRNA expression through epigenetic mechanisms. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B02.
Abstract B08: Tipping the balance: Factors that influence the ER signaling network in breast cancer
Authors: Jasper Jeff S. 
Published: August 2014

Abstract
Our lab has generated a tamoxifen resistant cell line (TamR) from MCF7 cells by serial passage in a nude xenograft model in the presence of tamoxifen. The TamR tumor model is stimulated by tamoxifen and does not require estradiol for growth. Transcriptional control of ER in this model is shifted to a ligand-independent state as ER target genes are basally increased and do not induce much higher with estradiol or tamoxifen. We hypothesized that the transcriptional program of ER was altered and that candidate factors could be identified with DNase Hypersensitivity analysis by DNase-Seq. Following Identification of DNase Hypersensitivity Regions, motif enrichment analysis, footprinting, and comparison to to known ChIP-Seq data were performed. These analyses indicate a an increased role for the FOXA family members and RNA-Seq indicates a dramatic upregulation of the FOXA2 transcript. Studies are ongoing to determine the relevance of FOXA2 in tamoxifen resistance and impact on the ER transcriptional program.
Citation Format: Jeff S. Jasper. Tipping the balance: Factors that influence the ER signaling network in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B08.
Abstract B11: Coupling between the DNA methylation and the alternative splicing
Authors: Mauger Oriane , Muchardt Christian , Batsché Eric 
Published: August 2014

Abstract
Pre-messenger RNAs (pre-mRNAs) maturation is initiated cotranscriptionally and chromatin-borne information participates in alternative splicing. We have found recently that elevated levels of trimethylation of histone H3 on Lys9 (H3K9me3) and the chromodomain protein HP1γ are a characteristic of the alternative exons of several genes including CD44 (Saint-André et al. 2011). On this gene, we have shown that the endogenous RNA interference pathway is involved in the H3K9me3 targeting on the variant exons through the recruitment of the nuclear argonaute proteins (AGO1 or AGO2) (Ameyar-Zazoua et al. 2012).
Because the DNA methylation is an epigenetic mark accompanying the transcriptional silencing, we now explore whether the DNA modification into the active genes could play a role in the regulation of the alternative splicing.
Studying the transcriptome and the genome of murine ES cells, allowed us to show that the enzymes that methylate DNA (DNMT1, 3a and 3b) regulate the splicing of many genes. In Hela cells the DNMT1 depletion causes a decrease in the inclusion of alternative exons of CD44. Similar results were obtained after depletion of MBD1 and MBD2, two proteins that bind to methylated DNA. Together these results suggest that DNA methylation regulates splicing of CD44 by a direct mechanism involving MBD1 and MBD2. The disregulation of the DNA methylation on CpGs is a hallmark of the tumorigenesis. However, the effect of DNA methylation changes within coding regions of the genes is poorly understood. We used the well-known model of breast tumor progression based on the MCF10A cells, to investigate the changes into the DNA methylation of the CD44 coding region. We found that the intragenic DNA methylation is modified between the MCF10A parental cells and the derived DCIS and CA1A transformed cells and this is correlated with the inclusion of the CD44 alternative exons. Altogether these results suggest that modifications of DNA methylation could contribute to the disregulations of alternative splicing decisions contributing to the tumor progression.
Ameyar-Zazoua M, Rachez C, Souidi M, Robin P, Fritsch L, Young R, Morozova N, Fenouil R, Descostes N, Andrau JC, Mathieu J, Hamiche A, Ait-Si-Ali S, Muchardt C, Harel-Bellan A, Batsché E (2012) Argonaute proteins couple chromatin silencing to alternative splicing. Nat. Struc. Mol. Biol 19:998-1004.
Saint-André V., Batsché E., Rachez C. and Muchardt C. (2011) Histone H3 lysine 9 tri-methylation and HP1γ favor inclusion of alternative exons. Nat. Struc. Mol. Biol 18:337-44.
Citation Format: Oriane Mauger, Christian Muchardt, Eric Batsché. Coupling between the DNA methylation and the alternative splicing. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B11.
Abstract B16: Phenotypic plasticity in the EML cell culture system as a result of HSP90 inhibition
Authors: Napper Jennifer , Sollars Vincent E. 
Published: August 2014

Abstract
The process of canalization whereby phenotypic traits are buffered against stochastic fluctuations to preserve the evolutionarily advantageous “normal” level can be potentially exploited during cancer progression. Release of canalization through pharmacologic or genetic down-regulation of Hsp90 removes this buffer and increases variation, allowing for rapid changes in traits as evidenced in Drosophila, Arabidopsis, and maize. If cancer is viewed as a Darwinian struggle of the premalignant cell to acquire the hallmarks of a fully malignant cell or be extinguished, then increasing variation or heterogeneity has a beneficial effect on the fitness of the premalignant cell. It is the goal of this work to test the hypothesis that Hsp90-derived canalization, though its ability to buffer phenotypic variance and thus reduce cell plasticity, is involved in hematopoietic cell differentiation. Furthermore, we wish to determine if the canalization mechanism has an epigenetic component. We are currently using a murine hematopoietic stem cell culture system, EML cells, to investigate this hypothesis. EML cells have been induced to differentiate into macrophage and granulocyte lineages with and without pharmacologic inhibition of HSP90 through 17-AAG. We found that 17-AAG treatment increases the ability of these differentiating cells to survive in a selective medium, during culturing conditions that suggest an epigenetic mechanism. If our hypothesis is true, then loss of canalization could be a potentially powerful mechanism driving cancer progression. Fully understanding the mechanism involved would allow for new therapeutic insights and provide vital information regarding the use of HSP90 inhibitors.
Citation Format: Jennifer Napper, Vincent E. Sollars. Phenotypic plasticity in the EML cell culture system as a result of HSP90 inhibition. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B16.
Abstract B23: Epigenetic regulation of OPA1 sensitizes hepatocellular carcinoma to sorafenib-induced apoptosis
Authors: Puszyk William Matthew , Dong Hui-Jia , Zhao Frank , Ogunwobi Olorunseun , Liu Chen 
Published: August 2014

Abstract
Sorafenib is a multi-kinase inhibitor used in the treatment of un-resectable hepatocellular carcinoma (HCC). Patient response to this therapy is variable. In this study we show that treatment with Sorafenib induces rapid mitochondrial fragmentation, which is associated with the deregulation of mitochondria-fusion-related protein OPA1, thus inducing apoptosis. Exposure of HCC cells or isolated mitochondria to Sorafenib induces cytochrome c release. Our data indicate that siRNA-mediated OPA1 knockdown significantly sensitizes HCC cells to Sorafenib-induced apoptosis. Furthermore, Sorafenib inhibits HCC xenograft tumor growth in vivo, and does not induce apoptosis in healthy primary hepatocytes. Murine xenograft tumor tissue samples revealed mitochondria fusion protein OPA1 expression levels are strongly associated with the sensitivity of HCC to sorafenib treatment. We have shown that Sorafenib suppresses the tumorigenesis of HCC through the induction of mitochondrial injury via OPA1. Epigenetic analysis of the OPA1 gene promoter indicates a role for DNA methylation in the suppression of OPA1 expression, and a potential biomarker which can be utilized for the identification of patients whom may benefit from treatment with Sorafenib. Our results provide new insights into the pathogenesis of HCC and suggest that OPA1 is a novel therapeutic target in patients with HCC.
Citation Format: William Matthew Puszyk, Hui-Jia Dong, Frank Zhao, Olorunseun Ogunwobi, Chen Liu. Epigenetic regulation of OPA1 sensitizes hepatocellular carcinoma to sorafenib-induced apoptosis. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B23.