bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A38: A functional connection between the SWI/SNF-BAF ATPase BRG1 and the tumor suppressor BRCA1 in DNA damage response
Authors: Zhang Ling , Chen Hua , Gong Feng 
Published: August 2014

Abstract
We and others have shown that the SWI/SNF (BAF) chromatin remodeling complex plays a role in the repair of UV-induced DNA damage. It was proposed that chromatin remodeling activities are utilized to increase the accessibility of NER machinery and checkpoint factors to the damaged DNA. It was demonstrated recently that BRCA1 contributes to UV damage response by promoting photoproduct excision, triggering post-UV checkpoint activation and post replicative repair. In this study, we show that BRCA1 rapidly binds to UV damage sites when cells are undergoing DNA synthesis. In contrast, two phosphorylated forms of BRCA1 do not accumulate at sites of UV damage. Depletion of BRG1, a core subunit of the human SWI/SNF-BAF complex, impairs the recruitment of BRCA1 to the damage sites and attenuates DNA damage induced BRCA1 phosphorylation. At UV lesions-stalled replication forks, BRG1 promotes RPA phosphorylation in response to UV irradiation, since UV-induced phosphorylation of chromatin bound RPA drops significantly when BRG1 is depleted in human cells. In addition, activation of ATR/ATM is attenuated when BRG1 is depleted. We propose that BRG1 functions upstream of BRCA1 and modulates its response to UV irradiation.
Citation Format: Ling Zhang, Hua Chen, Feng Gong. A functional connection between the SWI/SNF-BAF ATPase BRG1 and the tumor suppressor BRCA1 in DNA damage response. [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 A38.
Abstract A56: H3K9me3-based ChIP-seq analysis unveils global reprogramming in Cyclin D1-driven cellular senescence
Authors: Harajly Mohammad , Ghanem Noel , Saab Raya 
Published: August 2014

Abstract
Senescence is a permanent G1 cell-cycle arrest that can be triggered by acute stresses such as activated oncogenes and chemotherapeutic agents, and serves as a barrier to cancer development. Senescent cells exhibit distinct chromatin features compared with proliferating cells, known as senescence-associated heterochromatin foci (SAHF). These foci are enriched with histone H3 trimethylated at lysine 9 (H3K9me3), and are thought to impose a repressive state on regional genes. We performed genome-wide identification of elements associated with H3K9me3 by ChIP-seq technology, using an in vivo model of senescent pineal cells driven by Cyclin D1 oncogenic signaling, and compared them to non-senescent (Cyclin D1 expressing but p53-null) counterparts. We identified a set of genes whose H3K9me3 enrichment level was significantly changed (&gt;2-fold). We also analyzed gene expression profiles on Affymetrix transcriptome chips. We found that about 50% of genes associated with H3K9me3 exhibited significant reduction in expression, while other genes were either upregulated or showed no change in expression. Gene ontology analysis clustered the genes into several functional groups, including cell-cycle control, transcription regulation, protein metabolism, cellular differentiation, and cellular adhesion. Notably, the gene ontology clustering showed that genes associated with H3K9me3 in senescent cells clustered into distinctly different functional programs than those associated with H3K9me3 in cells that had bypassed senescence. Our data indicate that chromatin changes in cellular senescence are informative regarding a distinct functional phenotype of the senescent condition. The mechanisms by which such changes contribute to tumor suppression are under active investigation.
Citation Format: Mohammad Harajly, Noel Ghanem, Raya Saab. H3K9me3-based ChIP-seq analysis unveils global reprogramming in Cyclin D1-driven cellular senescence. [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 A56.
Abstract B05: The tumor suppressor gene pten regulates gene expression through histone H3.3 deposition and Daxx interaction
Authors: Benitez Jorge A. , Cavenee Webster K. , Furnari Frank B. 
Published: August 2014

Abstract
Sustaining proliferation is one of many capabilities acquired during tumor progression, where the PI3-kinase signaling pathway is a positive regulator of this trait and the tumor suppressor gene PTEN (phosphatase and tensin homology, deleted on chromosome ten) a negative regulator. Since PTEN deregulation is a central component of cancer progression, we decided to investigate how PTEN post-translational modifications modulate its function and protein interactions. We found that the histone chaperon protein Daxx (death domain-associated protein) associates with PTEN, in vivo and in vitro, and regulates PTEN stability through acetylation and ubiquitination. Moreover, we observed that PTEN regulates Histone 3.3 (H3.3 variant) deposition in the chromatin, by limiting Daxx interactions. We found an elevated H3.3-Daxx association in pten null cells, compared with pten-wt cells, correlating with a low H3.3 enrichment in the promoter of some driver tumor genes (Fos, Myc, Cyclin D1 and Bcl2) and an increased gene expression of them. We further demonstrated that this indirect gene expression regulation by PTEN is independent of its lipid-phosphatase activity. In conclusion, we hypothesize that PTEN may be mediating its tumor suppression function in part by regulating H3.3 deposition, and gene expression, through Daxx interaction.
Citation Format: Jorge A. Benitez, Webster K. Cavenee, Frank B. Furnari. The tumor suppressor gene pten regulates gene expression through histone H3.3 deposition and Daxx interaction. [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 B05.
Abstract B25: DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation
Authors: Pellacani Davide , Kestoras Dimitra , Droop Alastair P. , Frame Fiona M. , Berry Paul A. , Lawrence Mitchell G. , Stower Michael J. , Simms Matthew S. , Mann Vincent M. , Collins Anne T. , Risbridger Gail P. , Maitland Norman J. 
Published: August 2014

Abstract
Prostate cancer (CaP) is mostly composed of differentiated luminal cells, but contains a small subpopulation of undifferentiated basal cells (including stem-like cells), which is thought to be the driving force of CaP. In cancers, CpG island hypermethylation has been associated with gene downregulation, but the causal relationship between the two phenomena is still debated. This study aimed to understand the function and origin of CpG island hypermethylation in CaP, in the context of cancer hierarchy and differentiation. We have analyzed separately primary prostate basal and luminal cells derived from BPH and CaP. This allowed us to dissect the intra-tumor heterogeneity, and to understand the origin of gene downregulation and hypermethylation in CaP. We report that a set of genes commonly hypermethylated in CaP (including GSTP1) is: (i) downregulated as a result of prostate-specific epithelial differentiation in both CaP and benign prostatic hyperplasia (BPH); (ii) selectively hypermethylated in differentiated (luminal) cancer cells, process promoted by the hyperproliferating phenotype of these cells; (iii) actively expressed and methylation free in undifferentiated (basal) CaP cells. Downregulation and hypermethylation of these genes is not essential for tumor development or tumor expansion. Moreover, for all these genes, downregulation induced by prostate-specific differentiation, is independent of DNA hypermethylation, and is associated with detachment of RNA PolII from their promoter and reduction in histone marks associated with active transcription.
Citation Format: Davide Pellacani, Dimitra Kestoras, Alastair P. Droop, Fiona M. Frame, Paul A. Berry, Mitchell G. Lawrence, Michael J. Stower, Matthew S. Simms, Vincent M. Mann, Anne T. Collins, Gail P. Risbridger, Norman J. Maitland. DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation. [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 B25.
Abstract B30: Class I HDACs are mediators of smoke-carcinogen induced stabilization of DNMT1 and serve as promising targets for chemoprevention of lung cancer
Authors: Brodie Seth A. , Li Ge , El-Kommos Adam , Ramalingam Suresh S. , Behera Mahdusmita , Kowalski Jeanne , Gandhi Khanjan , Khuri Fadlo H. , Vertino Paula , Brandes Johann C. 
Published: August 2014

Abstract
Introduction: Epigenetic alterations have been identified as key events in the pathogenesis of non-small cell lung cancer (NSCLC). Previous studies have shown that smoke carcinogen exposure leads to increases in DNA-methyltransferase (DNMT1) protein expression, and subsequent epigenetic alteration - mediating early bronchial carcinogenesis. DNMT1 protein turnover is regulated by posttranslational modifications such as acetylation, phosphorylation and methylation. In lung cancer, increased levels of type I histone deacetylases (HDACs) HDAC1 and HDAC3 have been associated with poor outcomes. Clinically, HDAC inhibitors have shown promise for the treatment of advanced NSCLC.
Methods: In this study we use carcinogen exposed bronchial epithelial cells as a model of early carcinogenesis. We assayed these cells using various methods including soft-agar assays, methylation specific PCR and methylation array, siRNA knockdown, immunoblotting, co-immunoprecipitation and qPCR. We also analyzed a cohort of patient samples for expression of DNMT1 and HDACs by IHC.
Results: In this study, we describe that a close interaction between DNMT1 and class I histone deacetylases (HDAC)s after carcinogen exposure and in human lung cancer samples. We show that this interaction is associated with DNMT1 protein stabilization, can be disrupted with HDAC inhibition, and that HDAC inhibition leads to a loss of DNMT1 protein levels through an acetylation driven mechanism.
Conclusions: HDAC inhibition acts to epigenetically reprogram carcinogen exposed epithelia in part by blocking HDAC-DNMT1 interaction, thereby forcing the degradation of DNMT1. This highlights a possible role of HDAC inhibitors for the chemoprevention of lung cancer.
Citation Format: Seth A. Brodie, Ge Li, Adam El-Kommos, Suresh S. Ramalingam, Mahdusmita Behera, Jeanne Kowalski, Khanjan Gandhi, Fadlo H. Khuri, Paula Vertino, Johann C. Brandes. Class I HDACs are mediators of smoke-carcinogen induced stabilization of DNMT1 and serve as promising targets for chemoprevention of lung 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 B30.
Abstract B36: DNA methylation profiling describes Wilms tumor evolution from its precursor lesion
Authors: Charlton Jocelyn , Williams Richard , Alcaide-German Marisa , Sebire Neil , Popov Sergey , Pritchard-Jones Kathy , Beck Stephan 
Published: August 2014

Abstract
Wilms tumor (WT) is the most common pediatric renal cancer and represents a model of disruption in kidney development with observed lesions of undifferentiated embryonic kidney termed nephrogenic rests (NR) which are considered precursor lesions. Epigenetic dysregulation plays a large part in Wilms tumorigenesis as dysregulation of IGF2/H19 is the most common aberration observed in ~70% WT.
To provide new insights into the molecular evolution of WT from its precursor lesions, genome-wide CpG methylation, which has frequently been shown to alter gene expression in cancer, was studied using the Illumina HumanMethylation 450 BeadChip array. Matched normal kidney (NK), NR and WT were sampled from 30 patient nephrectomies. To ensure precise microdissection, DNA was extracted from formalin-fixed paraffin embedded tissue after histological analysis.
Analysis of methylation β-values revealed an increase in methylation variability in both the NR and WT tissue. Linear modeling further supported the role of NR as a precursor lesion however showed that, although morphologically similar to embryonic kidney, the NR tissue is a unique entity. Furthermore, drastic epigenetic restructuring is observed in NR tissue including large regions of hyper- and hypomethylation previously associated with cancer tissue. This novel data suggests the NR has a cancer-like methylome. Further changes in DNA methylation were observed upon evolution of NR to WT. These ‘late event' methylation variable positions have the potential to be developed into an assay for differential detection of NR or WT in diagnostically challenging cases.
These results lead us to propose that during Wilms tumorigenesis, NR are prevented from completing nephrogenesis and continue divergent evolution into a separate entity distinct from the embryonic kidney. These NR are precancerous lesions that then evolve into WT.
Citation Format: Jocelyn Charlton, Richard Williams, Marisa Alcaide-German, Neil Sebire, Sergey Popov, Kathy Pritchard-Jones, Stephan Beck. DNA methylation profiling describes Wilms tumor evolution from its precursor lesion. [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 B36.
Abstract B56: DNA demethylation in gene bodies is of therapeutic significance
Authors: Zhang Han Han , Yang Xiaojing , Carvalho Daniel D. De , Jones Peter A. , Liang Gangning 
Published: August 2014

Abstract
Reversal of aberrant promoter hypermethylation and associated gene silencing has been the primary focus of epigenetic therapy. Recently, gene body methylation has been implicated as having a functional role in the regulation of gene expression; however it is unclear how gene body methylation changes might contribute to the therapeutic effects of epigenetic therapy. To investigate the role of DNA demethylation in inducing gene expression changes in a comprehensive way, we treated the HCT116 colon cancer cell line with 5-Aza-2′-deoxycytidine (5-Aza-CdR) transiently for 24 hours and monitored changes in gene expression and DNA methylation levels at gene bodies and promoters for up to 42 days after treatment using 450K Infinium DNA methylation arrays and expression arrays. We observed that probes that became demethylated and subsequently regained methylation did at different rates. As we expected, demethylation of methylated promoters is negatively correlated with expression (R2≤ -0.75) and considerable demethylation of promoters (485) and the associated gene reactivation could be maintained for up to 42 days after drug treatment. Most of these genes are de novo methylated and their expression is down-regulated in primary colon cancers in the TCGA database. Strikingly, a group of genes shows a positive correlation between demethylation of gene bodies and down-regulation of gene expression after treatment (R2≥ 0.75). Four hundred ninety eight have fast rebound methylation kinetics and decreased expression and they are enriched for genes involved in metabolic process which are over-expressed in primary colon cancer tissues. Furthermore, 494 genes with sustained down-regulation of gene expression maintained their demethylated status and those are enriched for de novo methylation targets and over-expressed genes in colon cancer.
Our results demonstrate that DNA demethylation at gene bodies induced by 5-Aza-CdR can be of therapeutic significance by resulting in the down-regulation of genes that are overexpressed in cancers. Our findings also confirm that demethylation treatment could potentially cause prolonged reactivation of genes that are silenced by promoter methylation while simultaneously down-regulating genes that are overexpressed and have body methylation. Together, demethylation of gene bodies may confer therapeutic benefit in addition to demethylation of gene promoters.
Citation Format: Han Han Zhang, Xiaojing Yang, Daniel D. De Carvalho, Peter A. Jones, Gangning Liang. DNA demethylation in gene bodies is of therapeutic significance. [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 B56.
Abstract PR08: mSWI/SNF (BAF) complexes facilitate decatentation of DNA by topoisomerase IIα
Authors: Dykhuizen Emily , Hargreaves Diana , Miller Erik , Cui Kairong , Korshunov Andrey , Kool Marcel , Pfister Stefan , Cho Yoon-Jae , Zhao Keji , Crabtree Gerald 
Published: August 2014

Abstract
Recent exon sequencing studies of human tumors have revealed frequent mutations in subunits of BAF (mSWI/SNF) complexes. Here we find a novel function for BAF complexes in decatenating newly replicated sister chromatids, which is necessary for proper chromosome segregation during mitosis. We find that deletion of Brg1 leads to anaphase bridge formation and stalling in G2/M phase. In addition, we find that Brg1 point mutants identified from medulloblastoma and Burkitt's lymphoma patients have compromised ATPase function and that their expression similarly results in G2/M arrest and anaphase bridge formation. The G2/M arrest is rescued by caffeine, a known inhibitor of ATM/ATR, key regulators of the decatenation checkpoint, and also by expression of the TopoIIα point mutant, S1524A, which fails to initiate the decatenation checkpoint. Endogenous BAF complexes directly interact with endogenous TopoIIα and are required for TopoIIα binding to about 12,000 sites over the genome. Similarly, cells expressing the oncogenic Brg1 point mutants have compromised TopoIIα binding at Brg1-dependent TopoIIα binding sites. These studies indicate that the ability of TopoIIα to prevent DNA entanglement at mitosis requires BAF complexes and suggest that this activity contributes to the role of Brg1 as a tumor suppressor.
This abstract is also presented as Poster A36.
Citation Format: Emily Dykhuizen, Diana Hargreaves, Erik Miller, Kairong Cui, Andrey Korshunov, Marcel Kool, Stefan Pfister, Yoon-Jae Cho, Keji Zhao, Gerald Crabtree. mSWI/SNF (BAF) complexes facilitate decatentation of DNA by topoisomerase IIα. [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 PR08.
Abstract A04: HOXB13 regulates androgen receptor expression in prostate cancer
Authors: Chen Shuangling , Isaacs William B. 
Published: August 2014

Abstract
The androgen receptor (AR), a member of the nuclear receptor superfamily of ligand-regulated transcription factors, plays a pivotal role in the initiation and progression of prostate cancer. HOXB13, a prostate-specific homeodomain-containing transcription factor, interacts with AR to regulate the cellular response to androgens (Norris et al. Mol Cell 2009). The overexpression of HOXB13 in LNCaP and VCaP cells led to an increased expression of AR at the mRNA and protein levels; upon the reduction of endogenous HOXB13 by siRNA in LNCaP cells and VCaP cells, the amount of AR decreased at the mRNA and protein levels. Conversely, when AR was knocked down with siRNA in LNCaP cells, the level of HOXB13 proteins increased but not mRNA level, indicating that HOXB13 promotes the expression of AR, and AR promotes HOXB13 degradation. HOXB13 promoting AR expression might be one of the mechanisms by which HOXB13 regulates AR function.
Note: This abstract was not presented at the conference.
Citation Format: Shuangling Chen, William B. Isaacs. HOXB13 regulates androgen receptor expression in prostate cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A04.
Abstract A31: Regulation of ErbB4 receptor tyrosine kinase by the SUMO system
Authors: Korhonen Anna , Sundvall Maria , Vaparanta Katri , Elenius Klaus 
Published: August 2014

Abstract
The members of the ErbB family (EGFR/ErbB1, ErbB2, ErbB3, and ErbB4) of receptor tyrosine kinases (RTK) regulate key cellular processes including proliferation, differentiation, and survival, and play critical roles in several human malignancies. The alternatively spliced ErbB4 JM-a isoform was the first RTK found to signal by a mechanism involving proteolytic release of an intracellular receptor domain (ErbB4 ICD). The released ErbB4 ICD can translocate into the nucleus, where it functions as a transcriptional coregulator. ErbB4 ICD has been shown to regulate mammary epithelial development in vivo. Furthermore, nuclear ErbB4 immunoreactivity is frequently observed in clinical breast cancer samples. Although these findings suggest that ErbB4 signaling via ICD is biologically significant, little is known about the regulation of ErbB4 ICD functions or cellular localization.
We hypothesized that the soluble ErbB4 ICD is likely to be regulated by different mechanisms than the ones controlling conventional RTK signaling. One regulatory mechanism that is often employed by nuclear proteins is the small ubiquitin-like modifier (SUMO) system. SUMO proteins modify protein substrates covalently, and alter their function through changes in activity, stability, or cellular localization.
Here, we demonstrate that ErbB4 ICD is modified by SUMO-1 and SUMO-3. Full-length ErbB4 was not sumoylated, indicating that SUMO is a specific regulatory modification for the soluble ICD. By using site-directed mutagenesis followed by sumoylation assays, we mapped the major SUMO acceptor site in ErbB4. No differences were found between wild type and sumoylation deficient mutant of ErbB4 in biochemical assays measuring the tyrosine kinase activity of ErbB4, or activation of canonical RTK signaling pathways downstream of ErbB4. However, we showed that protein inhibitor of activated STAT3 (PIAS3), a SUMO E3 ligase that could stimulate the sumoylation, modulated the transcriptional coregulatory activity of ErbB4 ICD in luciferase reporter assays, as well as the function of ErbB4 ICD in mammary epithelial cell differentiation. Based on these findings we propose that the SUMO system regulates the nuclear signaling of ErbB4 ICD.
Citation Format: Anna Korhonen, Maria Sundvall, Katri Vaparanta, Klaus Elenius. Regulation of ErbB4 receptor tyrosine kinase by the SUMO system. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A31.