bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3331: PID1, a candidate tumor suppressor in pediatric and adult brain tumors, is a novel interacting partner for a cell surface receptor
Authors: Erdreich-Epstein Anat , Ren Xiuhai 
Published: July 2017

Abstract
BACKGROUND: PID1 is higher in fat from obese patients and is an inhibitor of insulin receptor signaling. We reported that PID1 is a novel inhibitor of medulloblastoma and glioma cell growth, and its mRNA level is highly correlated with survival across multiple independent datasets of these tumors. PID1 harbors a phosphotyrosine binding domain and is predicted to interact with proteins harboring NPXY motifs. We therefore hypothesized that PID1 will interact with phosphotyrosine-binding (PTB) domain containing protein(s) that may be important in brain tumors, and will modulate its/their signaling. Here we report PID1 interactions with one of these proteins and determine its biological consequences.
METHODS: Experiments consisted of immunoprecipitations, transient transfections, and western blotting. Functionally, assays included cell culture, flow cytometry for proliferation using BrdU/7AAD and apoptosis using AnnexinV/7AAD. Plasmids were pCMV-AN-HA-PID1(2) or control or the protein of interest in pcDNA3.1. Cell lines used were glioblastoma, medulloblastoma, atypical teratoid rhabdoid (ATRT), HEK293, and cells deficient or intact in PID1.
RESULTS: We demonstrate co-immunoprecipitation of PID1 with a receptor that is considered important in cancer. Immunoprecipitation was both in HEK293T cells overexpressing both proteins and in native brain tumor cell lines with/without overexpression. While tyrosine in the NPXY motifs was not required for the interaction, mutating the kinase domain of the receptor or overall inhibition of tyrosine phosphorylation impaired the interaction with PID1. Different domains in PID1 differentially co-immunoprecipitated with the receptor. Interestingly, mouse embryo fibroblasts without PID1 showed increased growth factor-dependent tyrosine phosphorylation of this protein and increased growth factor-induced proliferation. Identity of the receptor will be disclosed at the meeting.
CONCLUSIONS: These data point to PID1 as a novel interacting partner and regulator of this receptor’s biological effects and signaling in brain tumors.
Note: This abstract was not presented at the meeting.
Citation Format: Anat Erdreich-Epstein, Xiuhai Ren. PID1, a candidate tumor suppressor in pediatric and adult brain tumors, is a novel interacting partner for a cell surface receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3331. doi:10.1158/1538-7445.AM2017-3331
Abstract 3334: The FGFR4-388Arg variant exerts pro-tumorogenic effects in lung cancer by inducing an EMT phenotype
Authors: Quintanal-Villalonga Álvaro , Suárez Rocío , Ojeda-Márquez Laura , Ponce-Aix Santiago , Carnero Amancio , Paz-Ares Luis , Ferrer Irene , Molina-Pinelo Sonia 
Published: July 2017

Abstract
The FGFR4-388Arg allele, where an arginine substitutes a glycine in the 388 codon of the FGFR4 gene, has been associated to poorer patient outcome in different tumor types. In lung cancer, the variant has been related to shorter overall survival in adenocarcinoma (ADC) patients, while no relationship with squamous cell carcinoma prognosis (SCC) has been reported. Mechanistically, the FGFR4-388Arg variant has been related to increased MAPK pathway activation and to EMT in prostate cancer in vitro models. Furthermore, the variant has been associated with higher STAT3 signaling in murine models of breast and lung cancer. However, so far the molecular biology for this FGFR4 variant in lung cancer patients has not been addressed.
We overexpressed the FGFR4-388Gly and FGFR4-388Arg variants in lung cancer cell lines from different histologic backgrounds and performed tumorogenicity surrogate assays and downstream signaling activation assessment. In the generated stable cell lines, we also determined the expression of EMT markers. Furthermore, we determined the FGFR4 variant and the FGFR4 and N-cadherin mRNA expression in a cohort of NSCLC patients (N=65) and correlated these data to patient outcome.
We reported that FGFR4-388Arg increases tumorogenicity in lung cancer cell lines. Mechanistically, these functional effects seem to be mediated by MAPK and STAT3 overactivation and by the induction of an EMT phenotype, which includes N-cadherin increased expression. In fact, this induction of N-cadherin protein expression by the FGFR4-388Arg variant seems to be responsible for the pro-oncogenic effects reported. In NSCLC patient tumor samples, the FGFR4-388Arg variant correlates with higher N-cadherin expression and with poorer survival.
In conclusion, the FGFR4-388Arg variant is a potential prognostic biomarker in NSCLC, including ADC and SCC patients. This variant increases tumorogenesis through the activation of MAPK and STAT3 signaling pathways and through the promotion of an EMT phenotype.
Citation Format: Álvaro Quintanal-Villalonga, Rocío Suárez, Laura Ojeda-Márquez, Santiago Ponce-Aix, Amancio Carnero, Luis Paz-Ares, Irene Ferrer, Sonia Molina-Pinelo. The FGFR4-388Arg variant exerts pro-tumorogenic effects in lung cancer by inducing an EMT phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3334. doi:10.1158/1538-7445.AM2017-3334
Abstract 3338: A role for FGFR4 in growth and survival of Ewing sarcoma cells
Authors: Montoya Justin J. , Wai Daniel H. , Lee David W. , Azorsa Peter A. , Pepper Oliver B. , Arceci Robert J. , Azorsa David O. 
Published: July 2017

Abstract
Ewing sarcoma is the second most common cancer of bone and soft tissue arising in children and young adults. Although the survival rate has improved for patients treated for localized disease, the survival rate for patients with metastatic tumor remains lower than 30%. In order to identify novel therapeutic targets and to better understand the genes involved in growth and survival of Ewing sarcoma, we employed a functional genomics approach based on siRNA screening. Four Ewing sarcoma cell lines, TC-32, TC-71, SK-ES-1 and RD-ES, were transfected with a library of siRNA targeting 287 cancer-associated genes. The resulting siRNA screening data for each cell line were normalized and statistical cut-offs were determined. The results indicated that siRNAs targeting Fibroblast Growth Factor Receptor 4, FGFR4 were among the most effective in reducing cell viability in all four of the Ewing sarcoma cell lines. Validation of the siRNA screens showed that siRNAs to FGFR4, reduced viability much greater that those to FGFR1, FGFR2, or FGFR3. Furthermore, siRNA targeting FGFR4 were able to induce caspase 3 activity. FGFR4 protein is expressed on Ewing sarcoma cells as determined by western blot analysis, although expression levels were lower compared to FGFR4 expression on rhabdomyosarcoma cells. Targeting FGFR activity in Ewing sarcoma cells using a pan-FGFR inhibitors PD-173074 and BGJ-398 demonstrated that Ewing sarcoma cells were sensitive to FGFR inhibition. Furthermore, treatment of Ewing sarcoma cells with the selective FGFR4 inhibitor BLU9931 resulted in growth inhibition and decreased ERK signaling. These results indicate that FGFR4 may play an important role in growth and survival of Ewing sarcoma and could serve as a potential therapeutic target for this disease.
Citation Format: Justin J. Montoya, Daniel H. Wai, David W. Lee, Peter A. Azorsa, Oliver B. Pepper, Robert J. Arceci, David O. Azorsa. A role for FGFR4 in growth and survival of Ewing sarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3338. doi:10.1158/1538-7445.AM2017-3338
Abstract 3343: RNA demethylase alkbh5 supports breast cancer growth and progression
Authors: Eedunuri Vijay Kumar , Subbarayalu Panneerdoss , Rajamanickam Subhapriya , Nourhan Abdelfattah , Onyeagucha Benjamin C. , Timilsina Santosh , Yadav Pooja , Rao Manjeet K. 
Published: July 2017

Abstract
N6-methyladenosine (m6A) is one of the most prevalent internal modifications in eukaryotic messenger RNA. This dynamic and reversible modification is installed by methyltransferase complex consisting of three subunits: Methyltransferase-like protein 3 (METTL3), Methyltransferase-like protein 14 (METTL14) and Wilms tumor 1-associating protein (WTAP), and erased by two independent demethylases, Fat mass and obesity associated protein (FTO) and AlkB homolog 5 (ALKBH5). RNA demthylase ALKBH5 has been reported to play vital roles in several biological processes. However, very little is known about the role of ALKBH5 in cancer in general and breast tumorigenesis in particular. In this study, we report that ALKBH5 promotes breast cancer growth and progression. Using in vitro and in vivo models, we show that silencing of ALKBH5 inhibits breast cancer growth and invasion. Importantly, our studies reveal that ALKBH5 mediates its pro-tumorigenic function by regulating several microtubule associated genes including KIF2C, PLK1, MAPRE1 and RCC2 that are critical for spindle formation or assembly during mitotic progression. Interestingly, ALKBH5 target genes KIF2C and MAPRE1 are highly expressed in breast cancer patients and their higher expression is strongly correlated with lower survival of breast cancer patients. We believe that an optimal level of RNA methylation of key target genes is critical for normal cell cycle progression and any alteration in the levels of RNA methylation may alter activity or expression of these genes resulting in unabated cell proliferation.
Citation Format: Vijay Kumar Eedunuri, Panneerdoss Subbarayalu, Subhapriya Rajamanickam, Abdelfattah Nourhan, Benjamin C. Onyeagucha, Santosh Timilsina, Pooja Yadav, Manjeet K. Rao. RNA demethylase alkbh5 supports breast cancer growth and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3343. doi:10.1158/1538-7445.AM2017-3343
Abstract 3344: AKT mediates transcriptional regulation of H3K4 demethylase in PTEN null prostate cancer
Authors: Khan Mohammad Imran , Rath Suvasmita , Khan Qateeb , Adhami Vaqar M. , Mukhtar Hasan 
Published: July 2017

Abstract
One of the common contributors to the pre-disposition of most human cancers is inappropriate activation of AKT due to loss of its negative regulator PTEN. Activated AKT regulates changes in metabolic processes such as acetyl-CoA production that impacts chromatin. AKT phosphorylates a wide variety of histone modulating enzymes including acetyltransferases and methyltransferases resulting in their hyperactivation or inhibition. Therefore, understanding the impact of AKT inhibition on global histone modification would be ideal to identify novel histone modifiers regulated by AKT. We performed unbiased and comprehensive profiling of histone modifications in prostate specific PTEN knockout mice treated with an AKT inhibitor (Perifosine, 10mg/kg body weight daily for 4 weeks) and observed that AKT inhibition significantly induces di and tri methylation of H3K4, concomitant with reduction acetylation of H3K9. Changes in other histone modifications such as H3K36 and H3K79 methylation and acetylation were not observed. Mechanistically, we observed that AKT inihibiton reduces the expression of H3K4 methylation related histone demethylases KDM5 family, especially KDM5B expression at transcriptional level. Similar observations were noted at translational level also. To further understand the transcriptional regulation of KDM5B by AKT we focused on miR-137 and miR-138 as these have been shown to transcriptionally regulate H3K4 demethylases. We observed that AKT activation negatively regulated miR-137 but not miR-138 levels, which further transcriptionally represses KDM5B expression. Overexpression of miR-137 significantly reduced KDM5B and increased H3K4 di and tri methylation levels but failed to change AKT phosphorylation. Genetic knockdown of AKT or inhibition of AKT phosphorylation increased miR137 and reduced both KDM5B levels. Overall, we observed that AKT transcriptionally regulates KDM5B mainly via repression of miR137. Our data identify a mechanism by which PI3K/AKT signaling modulates the prostate cancer epigenome through regulating H3K4 methylation and KDM5B expression. Additional studies that assess the impact of AKT inhibiton on genome occupancy of H3K4 methylation will help in the identification of targets and devise novel strategies to enhance the therapeutic efficacy of PI3K/AKT inhibitors that are currently in clinical development.
Citation Format: Mohammad Imran Khan, Suvasmita Rath, Qateeb Khan, Vaqar M. Adhami, Hasan Mukhtar. AKT mediates transcriptional regulation of H3K4 demethylase in PTEN null prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3344. doi:10.1158/1538-7445.AM2017-3344
Abstract 3345: Selective killing of SMARCA2- and SMARCA4-deficient tumors by inhibition of EZH2: In vitro and in vivo preclinical models
Authors: Chan-Penebre Elayne , Armstrong Kelli , Drew Allison , Grassian Alexandra R. , Feldman Igor , Roche Maria , Ho Peter , Brach Dorothy , Raimondi Alejandra , Copeland Robert A. , Chesworth Richard , Smith Jesse J. , Ribich Scott A. 
Published: July 2017

Abstract
The histone methyltransferase EZH2 is the enzymatic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the methylation of H3K27 thereby repressing target gene transcription. EZH2 is amplified, overexpressed, or mutated in multiple cancer types, most notably Follicular Lymphoma (FL) and germinal center Diffuse Large B-cell Lymphoma (GCB-DLBCL). We previously reported that preclinical models of malignant rhabdoid tumors, which are deficient in the SWI/SNF core component INI1 (SNF5, SMARCB1), are selectively killed by potent and selective inhibitors of EZH2. Here we report another class of SWI/SNF-altered cancers named small cell carcinoma of the ovary hypercalcemic type (SCCOHT) that is dependent on EZH2 activity. SCCOHT is a very aggressive form of cancer that responds poorly to conventional therapy with a one-year overall survival rate of only 50%. Very few novel agents have been approved for this indication; thus there is a need for targeted therapeutics in SCCOHT. SMARCA4 and SMARCA2 are co-inactivated in this tumor type that has many rhabdoid features. We demonstrate that tazemetostat, an EZH2 inhibitor currently in phase 2 clinical trials, induces potent and selective killing in SMARCA2 and SMARCA4-deficient ovarian cell lines. In addition to small molecule inhibitor data, we conducted functional genomics studies with CRISPR pooled screening, and confirmed that SCCOHT is also sensitive to CRISPR-mediated EZH2 gene ablation. Dose-dependent anti-tumor effects were observed upon tazemetostat treatment in SCCOHT xenografts deficient in both SMARCA2 and SMARCA4. We also report on additional non-ovarian tumor types with dual SMARCA2/SMARCA4 loss including NSCLC that exhibit EZH2 dependence representing additional potential therapeutic indications for tazemetostat treatment.
Citation Format: Elayne Chan-Penebre, Kelli Armstrong, Allison Drew, Alexandra R. Grassian, Igor Feldman, Maria Roche, Peter Ho, Dorothy Brach, Alejandra Raimondi, Robert A. Copeland, Richard Chesworth, Jesse J. Smith, Scott A. Ribich. Selective killing of SMARCA2- and SMARCA4-deficient tumors by inhibition of EZH2: In vitro and in vivo preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3345. doi:10.1158/1538-7445.AM2017-3345
Abstract 3349: A regulatory circuit HP1 gamma/miR-451a/c-Myc promotes prostate cancer progression
Authors: Huang Ruimin , Chang Cunjie , Liu Jiakuan , Huang Xiaojing , Shen Lan , Zhang Dianzheng , Yan Jun 
Published: July 2017

Abstract
Heterochromatin protein 1 gamma (HP1 gamma), as a reader of the histone codes, is involved in the determination of higher order of chromatin structure. It has also been implicated in carcinogenesis of various cancer types. However, the role of HP1 gamma in prostate cancer (PCa) progression and the underlying molecular mechanisms remain largely unknown. Using the public microarray data from GEO and TCGA database, we found that HP1 gamma was upregulated in PCa, comparing with benign prostate tissues. PCa patients with higher level of HP1 gamma had shorter disease-free survival, indicating that HP1 gamma level can serve as prognostic marker in PCa patients (p = 0.016). In addition, depletion of HP1 gamma by shRNA in PCa cells not only repressed proliferation and induced apoptosis, but also impaired tumorigenicity in vitro and in vivo. We also found that c-Myc was capable of upregulating HP1 gamma by directly binding to the E-box element in the first exon of HP1 gamma gene, and the upregulated HP1 gamma, in turn, repressed the expression of miR-451a by enhancing H3K9 methylation at the promoter region of miR-451a. Furthermore, reduction of miR-451a significantly reversed HP1 gamma loss-induced PCa cell apoptosis, whereas miR-451a overexpression repressed cell survival by targeting and downregulating c-Myc. The association among mRNA and protein expression levels of c-Myc, HP1 gamma and miR-451a were further confirmed in human clinical samples using Spearman correlation analysis. Therefore, we propose that an HP1 gamma/miR-451a/c-Myc regulatory circuit exists in PCa cells and this circuit plays a crucial role in PCa progression.
Citation Format: Ruimin Huang, Cunjie Chang, Jiakuan Liu, Xiaojing Huang, Lan Shen, Dianzheng Zhang, Jun Yan. A regulatory circuit HP1 gamma/miR-451a/c-Myc promotes prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3349. doi:10.1158/1538-7445.AM2017-3349
Abstract 3352: Genome-wide enhancer identify signature predictive of metastatic phenotypes in bladder cancers
Authors: Kim Sohyoung , Varticovski Lyuba , Lao Qizong , Baek Songjoon , Nickerson Michael L. , Sung Myong-Hee , Grontved Lars , Bethtrice Thompson , Theodorescu Dan , Agarwal Piyush K. , Dean Michael , Hager Gordon 
Published: July 2017

Abstract
In urothelial bladder cancer accurate identification of grade and stage is critical for optimal treatment to achieve robust disease control and long-term survival. However, among the initially superficial tumors, which are non-invasive and highly treatable, 20 to 25 % recur, progress to invasive tumors, and metastasize during the patients’ lifetime. Thus, the challenge is to provide risk stratification during the initial diagnosis in order to identify those patients who are unlikely to progress while offering radical therapy to those who are at risk. To address this issue, the field has heavily focused on the discovery of few mutations in potential driver genes. However, recent findings indicate that deregulation of enhancers can play a major role in cancer progression. In this study, we employed DNase-Seq to detect enhancer activities genome-wide in 16 bladder cancer cell lines (BLCs) that included three lineages (T24, UMUC3, 253J lineages) with different tumorigenic and metastatic potentials, and thus represent models of cancer progression and metastasis development. We analyzed the gain and loss of enhancer activity in each BLC lineages as well as in metastatic cell lines relative to non-metastatic cell lines. Our analysis in the T24 lineage revealed a striking feature, a dramatic loss of intronic and distal DHSs (DNase I Hypersensitive sites), during the initial transition to tumorigenic type. During metastatic progression, new enhancer classes emerged and there was an enrichment for association with target organ-specific genes. The analysis of differential DHSs between metastatic and non-metastatic BLCs identified an enhancer signature enriched with lost DHSs in metastatic BLCs where nearby genes were associated with cellular movement/invasion functions. Lost DHSs were also present near key factors such as PPARG, RXRA, FOXA1, TP63, and GATA3, which play a role in urothelial development and differentiation, and the transcription activity of those genes were correlated with the change of enhancer activity. This study identified a set of DHSs that are associated with cancer progression in bladder cancer, and provides a potential clinical application for developing prognostic markers to predict the risk of developing aggressive disease.
Citation Format: Sohyoung Kim, Lyuba Varticovski, Qizong Lao, Songjoon Baek, Michael L. Nickerson, Myong-Hee Sung, Lars Grontved, Thompson Bethtrice, Dan Theodorescu, Piyush K. Agarwal, Michael Dean, Gordon Hager. Genome-wide enhancer identify signature predictive of metastatic phenotypes in bladder cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3352. doi:10.1158/1538-7445.AM2017-3352