bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 528: Identification of MYC as a novel repressor of miR-29 in pancreatic ductal adenocarcinoma
Authors: Kwon Jason , Quirin Kayla , Factora Tricia , Kota Janaiah 
Published: August 2018

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant disease with a dismal 5-year survival rate of 8%. The lack of effective therapies reinforces the need to better understand molecular mechanisms in PDAC. In our previous work, we found that downregulation of miR-29 is a common phenomenon of PDAC, and its restored expression had a potent tumor-suppressive effect in pancreatic cancer cells. However, the mechanism associated with the loss of miR-29 in PDAC has yet to be elucidated. In our initial work, using PDAC cell lines, we found that miR-29 is downregulated independent of KRAS. In an effort to understand the transcriptional factors mediating miR-29 repression, we selected several transcription factors that have a role in PDAC pathogenesis and binding sites in the miR-29 promoter region. siRNA mediated knockdown (KD) of three candidate transcription factors, SMAD4, MYC, and Gli3 revealed that the KD of MYC resulted in the highest gain of miR-29 expression (2-fold increase). Furthermore, MYC nuclear localization negatively correlates with miR-29 expression in various pancreatic cancer cell lines, and treatment of pancreatic cancer cells with small-molecule MYC inhibitor resulted in a dosage-dependent increase of miR-29 expression. miR-29a/b1 locus located on human chromosome 7 has two canonical MYC binding motifs upstream of the miR-29 transcription start site, which were functionally validated via luciferase assay. Finally, autophagy has been shown to be upregulated by MYC and is known to mitigate stressors of the integrated stress response (ISR) pathway in cancer. In our previous work, we showed that miR-29 blocks autophagy in pancreatic cancer cells. Consistently, we found miR-29 overexpression led to decreased cancer cell viability in combination with gemcitabine and induced the ISR as indicated by increased phospho-eIF2α. Taken together, our results demonstrate that MYC plays a key role in the regulation of miR-29 expression in pancreatic cancer. Furthermore, our data indicate the potential use of miR-29 as a novel therapeutic agent for PDAC, and these results could help form the basis for future studies to develop a more targeted approach of miR-29 therapeutic administration.
Citation Format: Jason Kwon, Kayla Quirin, Tricia Factora, Janaiah Kota. Identification of MYC as a novel repressor of miR-29 in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 528.
Abstract 531: Heterozygous IDH1
R132H/WT created by “single base editing” inhibits human astroglial cell growth by downregulating YAP
Authors: Wei Shuang , Wang Jie , Oyinlade Olutobi , Ma Ding Ma , Wang Shuyan , Xia Shuli 
Published: August 2018

Abstract
Mutations in the isocitrate dehydrogenase 1 (IDH1) gene have been identified in a number of cancer types, including brain cancer. The Cancer Genome Atlas project has revealed that IDH1 mutations occur in 70-80% of grade II and grade III gliomas. Until recently, most of the functional studies of IDH1 mutations in cellular models have been conducted in overexpression systems with the IDH1 wild type background. In this study, we employed a modified CRISPR/Cas9 genome editing technique called “single base editing”, and efficiently introduced heterozygous IDH1 R132H mutation in human astroglial cells (~20%). Compared with astroglial cells with IDH1 wild type, monoallelic IDH1 R132H mutation (IDH1R132H/WT) inhibited cell proliferation and promoted cell migration. Global gene expression analysis identified molecular targets and pathways altered by IDH1R132H/WT, including cell proliferation, extracellular matrix, and cell migration, consistent with our phenotype characterization. Global DNA methylation profiling showed hypermethylation as well as hypomethylation induced by IDH1R132H/WT. Using our mutated IDH1 models generated by genome editing, we identified novel molecular targets of IDH1R132H/WT, namely Yes-associated protein (YAP) and its downstream signaling pathway Notch, to mediate the cell growth-inhibiting effect of IDH1R132H/WT. Our findings are in line with the clinical observations that brain tumor patients with mutated IDH1 have a better prognosis. In summary, the “single base editing” strategy has successfully created heterozygous IDH1 R132H mutation that recapitulate the naturally occurring IDH1 mutant. Our isogenic cellular systems that differ in a single nucleotide in one allele of the IDH1 gene provide a valuable model for novel discoveries of IDH1R132H/WT-driven biological events.
Citation Format: Shuang Wei, Jie Wang, Olutobi Oyinlade, Ding Ma Ma, Shuyan Wang, Shuli Xia. Heterozygous IDH1R132H/WT created by “single base editing” inhibits human astroglial cell growth by downregulating YAP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 531.
Abstract 532: PELP1 and AIB1 (SRC-3) complexes promote cancer stem cell-associated phenotypes in ER+ breast cancer models
Authors: Truong Thu H. , Hu Hsiangyu , Temiz Nuri A. , Hagen Kyla M. , Girard Brian J. , Brady Nicholas J. , Schwertfeger Kathryn L. , Lange Carol A. , Ostrander Julie H. 
Published: August 2018

Abstract
Proline, glutamic acid, and leucine rich protein 1 (PELP1) is overexpressed in approximately 80% of invasive breast tumors. PELP1 dynamically shuttles between the nucleus and cytoplasm, but is primarily nuclear in normal breast tissue. However, altered localization of PELP1 to the cytoplasm is an oncogenic event that promotes breast cancer initiation and progression. Herein, we sought to identify interacting partners unique to cytoplasmic PELP1 and determine the mechanisms by which these interactions promote oncogenic PELP1 signaling. We identified AIB1 (amplified in breast cancer 1; also known as SRC-3 or NCOA3) as a novel binding partner of cytoplasmic PELP1 in both estrogen receptor-positive (ER+) and ER-negative cell lines. Cytoplasmic PELP1 expression elevated basal phosphorylation levels (i.e., activation) of AIB1, enhanced ALDH+ tumorsphere formation, and upregulated specific target genes independently of hormone stimulation. Direct manipulation of AIB1 levels using shRNA abrogated cytoplasmic PELP1-induced tumorsphere formation and downregulated cytoplasmic PELP1-specific target genes. SI-2, an AIB1 inhibitor, inhibited the PELP1/AIB1 interaction and decreased cytoplasmic PELP1-induced tumorsphere formation. Similar results were observed in a murine-derived MMTV-AIB1 tumor cell line (J110). Furthermore, in vivo syngeneic tumor studies showed that PELP1 knockdown in J110 cells resulted in increased survival of tumor-bearing mice as compared to mice injected with control cells. These studies suggest that manipulating PELP1 location or levels has the potential to mitigate tumor progression, particularly in the context of AIB1-mediated tumorigenesis. Taken together, our data demonstrate that cytoplasmic PELP1/AIB1-containing complexes function to promote advanced cancer phenotypes, including outgrowth of stem-like cells, associated with estrogen-independent breast cancer progression.
Citation Format: Thu H. Truong, Hsiangyu Hu, Nuri A. Temiz, Kyla M. Hagen, Brian J. Girard, Nicholas J. Brady, Kathryn L. Schwertfeger, Carol A. Lange, Julie H. Ostrander. PELP1 and AIB1 (SRC-3) complexes promote cancer stem cell-associated phenotypes in ER+ breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 532.
Abstract 5326: Differential methylation observed in cancer related genes between DNA samples from normal and obese individuals
Authors: Drennan Ryan , Culhane Nicolas , Poulin Matthew L. , Liu Zhenhua , Yan Liying 
Published: August 2018

Abstract
Based on research funded by The American Institute for Cancer Research, evidence is clear that weight can affect your risk of developing cancer. It is estimated that close to 1/3 of cancers that occur every year in the U.S. could be prevented by maintaining a healthy weight, being physically active and eating a nutritious diet. The body mass index (BMI) is defined as the body mass divided by the square of the body height and is typically expressed in kg/m2. BMI between 18.5 and 25 are considered normal while BMI of 25 to 30 is overweight and greater than 30 is considered obese. We have analyzed the DNA methylation levels of 18 individuals with BMI &gt;30, and compared them to 7 individuals with BMI between 18.5 and 25 utilizing three targeted Next-Gen Bisulfite Sequencing (tNGBS) panels that we have developed as well as with individual pyrosequencing assays. The three panels, FOXP3, Immunology and Cancer Panels, cover regulatory regions of 44 genes that include over 400 CpG sites in addition to a global methylation assay to the LINE1 promoter. The results show that seven gene regulatory regions and the LINE1 global methylation assay show significant differential methylation between the obese and the normal BMI samples. ESR1, PAPR1, EN1, LXH2, TFF1, FOXP3 and LINE1 were shown to be hypermethylated and CD3G was hypomethylated, with p-values ranging between 0.08 and 0.005. Larger sample cohorts can now be examined more thoroughly with individual pyrosequencing assays to further validate the findings.
Citation Format: Ryan Drennan, Nicolas Culhane, Matthew L. Poulin, Zhenhua Liu, Liying Yan. Differential methylation observed in cancer related genes between DNA samples from normal and obese individuals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5326.
Abstract 5328: Intergenic DNA methylation differences in ER- breast tumors from African American versus European American women
Authors: Buas Matthew F. , Chen Jianhong , Hu Qiang , Liu Song , Gong Zhihong , Higgins Michael J. , Ambrosone Christine B. 
Published: August 2018

Abstract
Incidence of estrogen receptor (ER)-negative breast cancer, a subtype with worse prognosis, is higher among African American (AA) versus European American (EA) women. The reasons for this gap remain poorly defined, but likely include differences in the prevalence and biological effects of known risk factors for ER- disease (eg. parity without breastfeeding and early menarche). These exposures may influence risk of ER- cancer via multiple mechanisms, one of which is epigenetic regulation of gene expression. Altered expression of genes controlling the proliferation and/or differentiation of luminal progenitor cells in the breast is likely to affect the propensity of such cells to give rise to ER- versus ER+ cancer. We previously conducted genome-wide DNA methylation profiling of 224 ER- tumor samples from 141 AA and 83 EA women in the Women's Circle of Health Study, and identified 374 differentially methylated loci (DML) by race. Our initial analysis focused on DMLs mapping to annotated genes, and revealed that a key pro-luminal transcription factor gene, FOXA1, was hypermethylated and repressed in AA compared to EA tumors. Moreover, parity without breastfeeding, more common among AAs, was associated with increased FOXA1 methylation. In this study, motivated by the biological importance of the non-coding genome, we focused on ~100 intergenic DML, and used paired 450K and RNA-seq data to assess the relationship between CpG methylation and RNA expression of genes located up to 50 kb away. Methylation at ten DML was significantly correlated with paired gene expression (FDR q&lt;0.05). For seven of these loci, lower methylation tracked with higher expression of the paired gene. One such CpG, hypomethylated in AA versus EA tumors, mapped to a putative enhancer element located 19 kb upstream of, and predicted to interact with, the promoter of LEMD1, a pro-tumorigenic cancer-testis antigen. Analysis of an independent set of 207 ER- breast cancers from TCGA confirmed that LEMD1 RNA expression was higher in AA compared to EA tumors (P=0.01, log2FC=0.95). Our findings suggest that epigenetic differences between AA and EA ER- tumors are linked to altered gene expression and may hold functional significance in breast cancer pathogenesis. Further studies are needed to extend these results to normal breast tissues from cancer-free women, and explore a potential role for FOXA1/LEMD1 epigenetic regulation in luminal progenitor cell homeostasis.
Citation Format: Matthew F. Buas, Jianhong Chen, Qiang Hu, Song Liu, Zhihong Gong, Michael J. Higgins, Christine B. Ambrosone. Intergenic DNA methylation differences in ER- breast tumors from African American versus European American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5328.
Abstract 533: OTULIN promotes resistance and metastasis upon chemotherapy in TNBC by activating Wnt/β-Catenin signaling
Authors: Wang Wei , Niu Jixiao , Zhang Bo , Wu Zhaohui 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC) or Basal-like breast cancer is characterized by worse prognosis than other breast cancer subtypes due to the rapid-arising therapeutic resistance accompanied by aggressive metastasis. The therapy-resistant tumor cells, including cancer stem-like cells (CSCs) with intrinsic resistance or tumor cells acquired resistance during treatments, could repopulate the primary tumors and serve as seeds for recurrent metastatic lesions. However, the molecular events orchestrating the innate and acquired therapeutic resistance are not completely understood. We found that the linear ubiquitin-specific deubiquitinase OTULIN is overexpressed in breast tumors, especially in the basal-like subtype, compared with normal breast tissues. Moreover, OTULIN overexpression significantly increased TNBC cells resistance to chemotherapy and is associated with shorter DFS in breast cancer patients. Mechanistically, we found genotoxic treatments activate OTLULIN, which promotes epithelial-to-mesenchymal transition (EMT) in TNBC cells through increased activity of Wnt/β-Catenin signaling. OTULIN overexpression significantly enhanced TNBC cells resistance to chemodrugs while inhibiting Wnt/β-Catenin signaling or OTULIN sensitized TNBC xenografts to Doxorubicin treatment in vivo. Our findings suggest that OTULIN-mediated Wnt/β-Catenin activation may increase TNBC therapeutic resistance and aggressiveness by promoting EMT. Targeting OTULIN and the chemotherapy-induced Wnt/β-Catenin activation may serves as promising strategy to mitigate drug resistance and reduce metastasis in TNBC patients receiving chemotherapy.
Citation Format: Wei Wang, Jixiao Niu, Bo Zhang, Zhaohui Wu. OTULIN promotes resistance and metastasis upon chemotherapy in TNBC by activating Wnt/β-Catenin signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 533.
Abstract 5330: DNA hypomethylation promotes carcinogenesis by inducing cryptic transcription
Authors: Lou Dan , Li Yanqiang , Martos Suzanne M. , Zhu Yan , Freeman Dana , Wang Zhibin 
Published: August 2018

Abstract
DNA methylation, regulate genomic processes and serve at the interface between genes and the environment, has long been recognized as the key event involved in cancer initiation and development. However, how exactly the role of DNA methylation and their epigenomic consequences underlying carcinogenesis remains to be elucidated. We previously reported that a division of labor between DNA methyltransferase (DNMT) (DNMT1 and DNMT3a/3b) to suppress distinct types of genome components. Additionally, allelic and biomodal methylation patterns have been revealed by using two bioinformatics methods. To determine how the DNA methylation affects the integrity of gene transcription, we applied the appropriate PRO-cap technique that detects 5'-capped RNA transcripts in wildtype (WT) mESCs and three mutant mESCs with altered DNMT: loss of DNMT1 (DNMT1-/- ; 1KO), loss of DNMT3a/3b (DNMT3a-/-/DNMT3b-/-; DKO) and loss of DNMT1 and DNMT3a/3b (DNMT1-/-/ DNMT3a-/-/DNMT3b-/-; TKO). With high quality of sequencing reads at high fold coverage and 150 millions of mapped reads for WT and mutant cells, our analyses revealed significant RNA transcripts alterations. By mapping global transcription start site (TSS) and chromatin dynamics, cryptic transcription of thousands of DNMT loss-induced non-annotated TSSs were observed. Some of the non-annotated TSSs were further confirmed in arsenic-treated malignant transformated cell line. Our results indicated that the alteration (completely loss or partially loss) of DNA methylation may promote the carcinogenesis by sabotaging the fidelity of gene transcription initiation.
Citation Format: Dan Lou, Yanqiang Li, Suzanne M. Martos, Yan Zhu, Dana Freeman, Zhibin Wang. DNA hypomethylation promotes carcinogenesis by inducing cryptic transcription [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5330.
Abstract 5331: Repression of TET genes and enhancement of DNA methyltransferase activity are critical for induction of aberrant DNA methylation
Authors: Takeshima Hideyuki , Niwa Tohru , Yamada Harumi , Yamashita Satoshi , Wakabayashi Mika , Ushijima Toshikazu 
Published: August 2018

Abstract
Chronic inflammation is deeply involved in the development of human cancers by inducing epigenetic alterations, such as aberrant DNA methylation. Among various inflammatory cytokines, the expression of Il1b, Tnf, and Nos2, is associated with induction of aberrant DNA methylation. However, the molecular mechanisms by which these cytokines induce aberrant DNA methylation remain unclear. Here, we show that the activation of the NF-kB signaling pathway, downstream of IL-1β and TNF-α, caused up-regulation of specific miRNAs, such as miR-20a, miR-26b, and miR-29c, and that these miRNAs caused repression of the Tet methylcytosine dioxygenases (Tet) genes, Tet1, Tet2, and Tet3. TET repression by overexpression of one of these miRNAs in cultured cells appeared to be insufficient for induction of aberrant DNA methylation as detected by an Infinium MethylationEPIC BeadChip array. However, triple knockout of TET genes induced strong DNA methylation at thousands of genomic loci. At the same time, exposure to nitric oxide, produced by Nos2, enhanced enzymatic activity of DNA methyltransferases (DNMTs). Treatment of cultured cells with nitric oxide induced weak DNA methylation at hundreds of genomic loci. These results show that both the repression of TET genes and enhancement of DNMT activity, induced by chronic inflammation, are critical for induction of aberrant DNA methylation. ''Vicious'' combination of such dysregulations might have a synergistic effect on induction of aberrant DNA methylation.
Citation Format: Hideyuki Takeshima, Tohru Niwa, Harumi Yamada, Satoshi Yamashita, Mika Wakabayashi, Toshikazu Ushijima. Repression of TET genes and enhancement of DNA methyltransferase activity are critical for induction of aberrant DNA methylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5331.
Abstract 5334: Spg20 (Spartin) promoter methylation identifies tumor B lymphocytes
Authors: Frazzi Raffaele , Simone Tonia De , Pistoni Mariaelena , Merli Francesco 
Published: August 2018

Abstract
Introductory sentence. The layer of regulation represented by gene promoter methylation is being investigated in Non-Hodgkin lymphoma (NHL) cell lines, primary B lymphocytes and peripheral blood mononuclear cells (PBMCs). The aim is to assess whether the panel of differentially methylated genes we previously identified is able to distinguish normal B lymphocytes from lymphoma cells.
Experimental procedures. Quantitative, gene-specific methylation assays. Immunosorting of human B lymphocytes. Proliferation assays. 5-azacytidine treatment. NHL-derived cell lines.
New data. Here we show that NHL-derived cell lines display a characteristic profile of promoter methylation on specific tumor suppressors and target genes. A panel of 9 target promoters was selected previously and assessed on a series of healthy and tumor primary B lymphocytes. 4 out of 5 NHL-cell lines show a highly methylated profile on KLF4, DAPK1 and SPG20, at variance with normal B lymphocytes (lymph-node derived) and PBMCs where these targets are completely unmethylated. Interestingly, PBMCs from healthy donors display the same methylation pattern as the one shown by B lymphocytes immunologically sorted from follicular hyperplasias. Spartin (SPG20) emerges here as a differentially methylated gene associated to lymphocyte malignancy, at variance with other tumor suppressors in our panel that show variability among different cell lines. SPG20 is completely or highly methylated in all the tested NHL-cell lines. According to this observation, SPG20 results not methylated in PBMCs as well as sorted non-tumor B lymphocytes. On the contrary, the methylation status of three different BCL6 CpG islands (assessed with the same technique) may vary among different cell lines. In order to investigate what's the functional role of these specific promoters methylation, we treated Toledo and NU-DUL-1 cell lines with the demethylating agent 5-azacytidine (5AZA). We observe that the dose-dependent inhibition of proliferation upon 5AZA is accompanied by a small but reproducible decrease in SPG20 and MZB1 promoter methylation. Experiments aimed at assessing any involvement of DNA methyltransferases DNMT1 and DNMT3a are currently ongoing.
Conclusions. Our data show a consistent methylation profile of 9 gene promoters on 5 different NHL-derived cell lines. Spartin emerges as a completely methylated promoter in the tested tumor cells. PBMCs show a consistent unmethylated profile of Spartin and of all the target genes. The epigenetic regulation of these genes in B-derived lymphomas warrants further investigation.
Citation Format: Raffaele Frazzi, Tonia De Simone, Mariaelena Pistoni, Francesco Merli. Spg20 (Spartin) promoter methylation identifies tumor B lymphocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5334.