bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5199: A novel role for BAP1 in development and tumor suppression
Authors: Owens Dawn A. , Kuznetsov Jeffim N. , Kurtenbach Stefan , Agüero Tristan , King Mary Lou , Harbour J. William 
Published: August 2019

Abstract
Uveal melanoma (UM) is the second most common form of melanoma and one of the most deadly types of cancer. Recent discoveries in our laboratory and others have led to a deeper understanding of the driver mutations UM. The initiating mutation that is present in virtually all UM occurs in one of four genes in the Gaq signaling pathway (the “Gaq” mutations) and result in sustained activation of proliferative signals. A second mutation occurs later in one of three genes – BAP1, SF3B1 or EIF1AX (the “BSE” mutations), which determines metastatic risk – BAP1 (high risk), SF3B1 (intermediate risk) or EIF1AX (low risk). Surprisingly, we recently discovered that the Gaq mutation and the subsequent BSE mutation occur very close in molecular time. This work suggests that Gaq mutations may cause epigenetic changes that predispose to BSE mutations. We have shown that BAP1-mutant UMs exhibit a de-differentiation and stem-cell like phenotype, suggesting that BAP1 may normally regulate differentiation programs during embryonic development. Consistent with this possibility, BAP1 loss in mouse is embryonic lethal. To study the role of BAP1 in early vertebrate development, therefore, we chose Xenopus laevis (African clawed frog), a widely used model for studying gene function during development. We found that targeted depletion of the Xenopus BAP1 protein (xBap1) causes a striking developmental phenotype affecting multiple germ layers, and that this phenotype is associated with disruption of super enhancers around differentiation genes that are normally maintained by BAP1. Taken together, these studies suggest that loss of BAP1 promotes tumor progression and metastasis, at least in part, by disrupting tightly controlled differentiation programs that govern cell identity. These findings may nominate new therapeutic targets in BAP1-mutant cancers.
Citation Format: Dawn A. Owens, Jeffim N. Kuznetsov, Stefan Kurtenbach, Tristan Agüero, Mary Lou King, J. William Harbour. A novel role for BAP1 in development and tumor suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5199.
Abstract 5203: Segregating activities of the estrogen receptor in gene regulation
Authors: Yang Mei , Zhang Zhao , Xu Kexin 
Published: August 2019

Abstract
Upon stimulation with its ligand estradiol (E2), the estrogen receptor (ER) obviously can induce both transcriptional activation and repression in breast cancer cells. Although the mechanism of gene activation has been extensively scrutinized, how ER targets are turned off is generally overlooked. Some theories have been proposed to explain the trans-suppression process, such as engagement of corepressors, physiological squelch of coactivators, or decommission of RNA Polymerase II, etc. However, none of these models really elucidate the intrinsic and external factors that segregate ER activities in transcriptional regulation. In this study, we identified a functional domain of ER, which is specifically required for E2-mediated gene repression. While the DNA-binding domain (DBD) was essential for the overall response to E2, deletion of AF2 fragment at C-terminus of ER specifically reverted the E2-repressed transcriptional program into E2-activated one. We further demonstrated that RNAs transcribed from these E2-repressed enhancers (eRNAs) act as the exterior determinants of ER activity in gene repression. In addition to stabilizing promoter-enhancer looping structure, these eRNAs recruit ER to particular chromatin loci, and facilitate the hierarchical formation of a functional complex responsible for transcriptional repression. Thus, our findings suggest that by targeting distinct functional domains of ER, we may be able to reprogram expression of a specific subset of ER targets, which play critical roles in conferring malignant phenotypes of breast cancer cells. Meanwhile, as a distinctive class of cis-acting elements besides chromatin regulatory regions, eRNAs help to refine ER-dependent transcriptional program that contributes to the development and progression of breast cancer.
Citation Format: Mei Yang, Zhao Zhang, Kexin Xu. Segregating activities of the estrogen receptor in gene regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5203.
Abstract 5213: A modified L-penetratin peptide targeting e2f-1, 2 and 3 is effective in combination with cisplatin or pemetrexed against prostate and lung cancer cell lines
Authors: Rather Gulam M. , Anyanwu Michael , Kerrigan John E. , Scotto Kathleen W. , Garbuzenko Olga , Minko Tamara , Szekely Zoltan , Bertino Joseph R. 
Published: August 2019

Abstract
Overexpression of the “activating” transcription factors, E2F1,2 and-3a induces genes involved in DNA synthesis and leads to cellular proliferation, tumor growth, and invasion. Therefore, inhibiting the overexpression of one or more activating E2Fs is a recognized target in cancer therapeutics. Dysregulation/overexpression of E2Fs is also controlled by deletion or mutations in the retinoblastoma protein in tumors. In our previous studies we showed that a novel penetratin conjugated 7-mer peptide (PEP) inhibited transcription of the E2F1, 2 and 3a by bounding tightly to E2F promoters. The PEP was cytotoxic at low micro molar concentrations to several malignant cell lines. As the PEP was unstable in vivo, the PEP was encapsulated in PEGylated liposomes (PL-PEP). Treatment of xenografts of the pRB negative small cell lung cancer H-69 and castrate resistant prostate cancer DU145 tumors propagated in mice with the PL- PEP, caused tumor regression. To increase stability and potency of the PEP, L-Arg in the PEP was replaced by D-Arg. Molecular simulation studies showed that the D-Arg PEP secondary structure is more stable than the L- Arg peptide structure in water. In vitro studies showed that the D-Arg PEP was more potent and more resistant to degradation by serum proteases than the L- form. As E2F is important for DNA repair, and for transcription of thymidylate synthase, we tested the effects of the PEP in combination with cisplatin, a DNA damaging drug and pemetrexed, a potent thymidylate synthase inhibitor. Combination studies of the D-ARG pep with cisplatin (in DU145, PC3, LnCap and 4T1) cells and with pemetrexed (in non-small cell lung cancer, H2009, H441, H1975 and H2228) resulted in synergistic cytotoxicity as determined by Chou-Talalay analysis.
Citation Format: Gulam M. Rather, Michael Anyanwu, John E. Kerrigan, Kathleen W. Scotto, Olga Garbuzenko, Tamara Minko, Zoltan Szekely, Joseph R. Bertino. A modified L-penetratin peptide targeting e2f-1, 2 and 3 is effective in combination with cisplatin or pemetrexed against prostate and lung cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5213.
Abstract 5215: Targeting of HOX-PBX binding in glioblastoma multiforme as a novel therapeutic treatment
Authors: Morgan Richard , Primon Monika , Shnyder Steven , Short Susan , Kaur Balveen , Hong Bangxing , Bagwan Izhar , Rogers William , Pandha Hardev S. 
Published: August 2019

Abstract
The HOX genes encode a family of transcription factors that play an essential role in embryonic patterning. They are also aberrantly expressed in numerous cancers, including glioblastoma (GBM). Three Amino Acid Loop Extension Homeobox (TALE) proteins act as important co-factors for HOX proteins, modulating their binding affinities to genomic targets. TALE proteins include the Pre-B-cell leukemia homeobox (PBX) proteins 1-4, which bind anterior HOX proteins, facilitating their nuclear entry and limiting their degradation. HTL00-1 is a 2nd generation hexapeptide drug that inhibits HOX-PBX dimer formation, and has been shown to induce rapid apoptosis in cancer cells, but not normal cells, through the rapid upregulation of genes including cFos, DUSP1, and EGR1. We have found that both HOX and TALE genes are markedly dysregulated in primary GBM tumors as well as in murine (GL261), adult (LN18, U87-MG, U251-MG) and pediatric (KNS42, SF188) GBM cell lines, all of which are sensitive to HTL-001. These genes were even more highly expressed in experimentally induced GBM cancer stem cells (CSCs) compared with parental lines, with a corresponding increase in sensitivity to HTL-001. We also investigated the in vivo activity of HTL-001 in Black 6 mice carrying GL-261 subcutaneous and orthotropic tumors with twice weekly intraperitoneal delivery. HTL-001 was shown to cross the blood brain barrier using Alexa660 labelled peptide, and significant anti-tumor activity was observed in both subcutaneous and orthotropic models with increased survival (p&lt;0.02 and p&lt;0.0078, respectively). Resected tumors from HTL-001 treated mice showed marked evidence of apoptosis, tumor vasculature disruption and focal necrosis compared to untreated tumors. Taken together, our findings indicate that HOX-PBX inhibition is a potential therapeutic target for adult and pediatric GBM patients.
Citation Format: Richard Morgan, Monika Primon, Steven Shnyder, Susan Short, Balveen Kaur, Bangxing Hong, Izhar Bagwan, William Rogers, Hardev S. Pandha. Targeting of HOX-PBX binding in glioblastoma multiforme as a novel therapeutic treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5215.
Abstract 5220: Transcription regulatory networks associated with luminal master regulator expression and breast cancer survival
Authors: Byun Jung S. , Singhal Sandeep , Park Samson , Yi Dae IK , Caban Ambar , Vohra Nasreen , Perez-Stable Eliseo J. , Napoles Anna , Gardner Kevin L. 
Published: August 2019

Abstract
The disparity in breast cancer burden of African Americans compared with European Americans is one of the most revealing instances in oncology associated with ethnicity. Recent studies demonstrated that there were highly intratumoral genetic heterogeneity and increased the frequency of basal subtypes among African Americans than European Americans. Because significant race-based disparities in breast cancer patients with hormone-receptor positive still persistent even after reflecting socio-economic status, there may be substantial roles playing by intrinsic biological factors contributing to the disparities. Transcriptional regulation governed by estrogen receptor plays critical roles in major changes in chromatin landscape that facilitate the assembly of other transcriptional complexes affecting mammary tumor initiation and proliferation. We investigated the estrogen receptor and its essential pioneer transcription factors how their expressions are associated with racial disparity with their prognostic significance. Co-expression analysis of estrogen receptor and its pioneer transcription factors suggest that ER-positive patients of women of European ancestry show much more favorable survival than women of African ancestry. Differential comparison of protein expression integrated with network-level gene expression analysis reveals significant differences in the predictive ability of the luminal master regulators based on race and survival. Moreover, we identified genes in the downstream of these master regulators that are highly correlated with race and survival. The comparative analysis of the predictive value of race-based cutoffs suggests that these master regulators of luminal differentiation have reduced transcriptional activity in the downstream regulatory network pathways in African ancestry. Functional characterization of the luminal master regulators and their downstream pathways may provide a better understanding of the intrinsic mechanisms that drive racial disparities in breast cancer survival.
Citation Format: Jung S. Byun, Sandeep Singhal, Samson Park, Dae IK Yi, Ambar Caban, Nasreen Vohra, Eliseo J. Perez-Stable, Anna Napoles, Kevin L. Gardner. Transcription regulatory networks associated with luminal master regulator expression and breast cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5220.
Abstract 5225: Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer
Authors: Tiwari Ritika , Manzar Nishat , Bhatia Vipul , Yadav Anjali , Carskadon Shannon , Gupta Nilesh , Zoubeidi Amina , Palanisamy Nallasivam , Ateeq Bushra 
Published: August 2019

Abstract
The Serine Peptidase Inhibitor, Kazal type 1 (SPINK1) overexpression represents the second-largest prostate cancer (PCa) subtype associated with increased risk of recurrence and poor prognosis. Regardless of molecular subtype, androgen-deprivation therapy (ADT) remains the mainstay treatment for locally advanced and metastatic PCa patients. However, majority of the treated individuals eventually progress to castration-resistant stage and a subset of these patients develop ADT-induced neuroendocrine prostate cancer. Despite evidences of detrimental effects of ADT on PCa, possible role of androgen signaling in SPINK1-mediated prostate oncogenesis remains unexplored. Here, we show that androgen receptor (AR) functions as a direct transcriptional repressor of SPINK1, and blocking AR signaling relieves its repression, leading to upregulation of SPINK1. In agreement, we observe an inverse association between SPINK1 levels and AR expression across multiple patient cohorts, and in neuroendocrine differentiated LNCaP cells. We show that AR and its corepressor, the RE1-silencing transcription factor (REST), occupy SPINK1 promoter and inhibits its transcription. On the other hand, in the absence of AR, lineage reprogramming factor SOX2 in turn binds to SPINK1 promoter leading to its positive transcriptional regulation in androgen-deprived conditions with concomitant increase in neuroendocrine markers. Additionally, stable knockdown of SPINK1 results in reduced epithelial-mesenchymal transition, decreased stemness and drug resistance. Collectively, our findings provide a plausible explanation to the paradoxical clinical outcomes of ADT, arising due to increase in SPINK1 levels. Finally, we emphasize the need to take a well-informed decision prior to ADT and develop alternative therapeutic strategies for castrate-resistant PCa patients.
Citation Format: Ritika Tiwari, Nishat Manzar, Vipul Bhatia, Anjali Yadav, Shannon Carskadon, Nilesh Gupta, Amina Zoubeidi, Nallasivam Palanisamy, Bushra Ateeq. Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5225.
Abstract 5228: Acute depletion of CTCF disrupts enhancer-promoter regulation ofMYCin B-cell acute lymphoblastic leukemia
Authors: Li Chunliang , Zhang Yang 
Published: August 2019

Abstract
Acute lymphoblastic leukemia (ALL), including B-ALL and T-ALL, is the most common childhood cancer and the leading cause of cancer death in children and young adults. Comprehensively genomic sequencing strategies have successfully sub-classified ALL based on genetic alterations including chromosomal rearrangement and aberrant gene mutations, of which frequent coding mutations of CTCF were discovered. However, the function of CTCF in ALL was not clearly defined yet. In a cohort of 264 human pediatric B-ALL patients, particularly in those carrying CTCF loss-of-function mutations, we identified a positive correlation of mRNA expression between CTCF and MYC. Then we integrated the miniAID-mClover3 cassette to the both alleles of endogenous human CTCF locus, which allows acute auxin-mediated degradation of the CTCF protein in a human pediatric B-ALL cell line. By employing combination strategies including whole transcriptome analysis and Capture-C, we discovered that only small number of genes were differentially expressed in CTCF depleted cells, among which MYC and it's downstream genes, not other B-ALL associated oncogenes, were specifically enriched. Mechanically, chromatin interaction capture assay reveals that acute depletion of CTCF primarily disrupted direct interaction between MYC promoter and its distal enhancer residing ~1.8 Mb downstream, subsequently down-regulating target genes in human B-ALL cancer cells. Thus, CTCF/MYC regulation axis is essential in B-ALL development.
Citation Format: Chunliang Li, Yang Zhang. Acute depletion of CTCF disrupts enhancer-promoter regulation ofMYCin B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5228.
Abstract 5230: Modulation of SF3B1 causes global intron retention and downregulation of the B-cell receptor pathway in chronic lymphocytic leukemia
Authors: Han Qimei , Wang Jianbo , Shull Austin Y. , Shi Fang , Deng Libin , Choi Jeong-Hyeon , Park Eun-Jeong , Tu Shuo , Pei Lirong , Awan Farrukh T. , Bollag Roni , Bryan Locke J. , Xin Hong-bo , Lagisetti Chandraiah , Webb Thomas R. , Jin Victor , Shi Huidong 
Published: August 2019

Abstract
Splicing factor SF3B1 is frequently mutated in chronic lymphocytic leukemia (CLL) patients and has been suggested as a potential therapeutic target. In this study, we demonstrated that SF3B1 modulator sudemycin D6 (SD6) effectively inhibits cell growth and induces apoptosis in CLL cells. RNA sequencing analysis revealed significant increases in global intron retention in SD6-treated CLL cells. Pathway analysis of the genes associated with increased intron retention suggested that B-cell receptor (BCR) and PI3K signaling pathways were among the most important pathways being affected by SD6. The increases in intron retention were inversely correlated with decreases in mRNA and protein levels of the affected BCR/PI3K pathway molecules including BLNK, BTK, AKT, PLCγ2, and PI3Kδ. SD6 treatment also induced a time-dependent exon-skipping event in MCL-1 mRNA and resulted in significant down-regulation of another anti-apoptotic gene TRAF1, thus collectively contributing to the SD6-induced apoptosis. Furthermore, SD6 treatment can overcome the pro-survival and pro-growth signals and synergize with established CLL therapies ibrutinib, idelalisib, and venetoclax to induce apoptosis in primary CLL cells co-cultured with bone marrow stromal cells and T-cell-derived cytokines. Finally, in vivo treatment with SD6 at 10mg/kg/day for 7 days significantly inhibited the growth of xenograft tumors that were established by subcutaneous inoculation of 5×106 MEC1 CLL cells into NOD mice. Collectively, these results provide a strong rationale for the future clinical development of spliceosome modulators and potential combination therapies for the treatment of CLL.
Citation Format: Qimei Han, Jianbo Wang, Austin Y. Shull, Fang Shi, Libin Deng, Jeong-Hyeon Choi, Eun-Jeong Park, Shuo Tu, Lirong Pei, Farrukh T. Awan, Roni Bollag, Locke J. Bryan, Hong-bo Xin, Chandraiah Lagisetti, Thomas R. Webb, Victor Jin, Huidong Shi. Modulation of SF3B1 causes global intron retention and downregulation of the B-cell receptor pathway in chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5230.
Abstract 524: HMGB1-activated IRF3 and NF-κB contributes to UV radiation-induced immune suppression by upregulating PD-L1
Authors: Wang Wei , Chapman Nicole , Zhang Bo , Li Mingqi , Fan Meiyun , Laribee R. Nicholas , Zaidi M. Raza , Pfeffer Lawrence , Chi Hongbo , Wu Zhaohui 
Published: August 2019

Abstract
Solar ultraviolet radiation (UVR) suppresses skin immunity, which facilitates skin lesion initiation and establishment by promoting immune evasion. It is unclear whether immune checkpoints are involved in the modulation of skin immunity by UVR. Here we report that the expression of immune checkpoint molecule PD-L1 was significantly increased in melanocytes and melanoma cells upon UVR exposure. The damage-associated molecular patterns molecule HMGB1 was secreted by melanocytes and keratinocytes upon UVR, which subsequently activated the RAGE (receptor for advanced glycation endproducts) receptor to promote the NF-κB and IRF3-dependent transcription of PD-L1 in melanocytes. We also found that UVR exposure significantly reduced the susceptibility of melanoma cells to CD8+ T cell-dependent cytotoxicity, which was mitigated by inhibiting the HMGB1/TBK1/IRF3/NF-κB cascade or blocking the PD-1/PD-L1 checkpoint. Taken together, our findings demonstrate that UVR-induced PD-L1 upregulation contributes to the immune suppression in the skin microenvironment, which may promote immune evasion of oncogenic cells, and melanoma initiation and progression.
Citation Format: Wei Wang, Nicole Chapman, Bo Zhang, Mingqi Li, Meiyun Fan, R. Nicholas Laribee, M. Raza Zaidi, Lawrence Pfeffer, Hongbo Chi, Zhaohui Wu. HMGB1-activated IRF3 and NF-κB contributes to UV radiation-induced immune suppression by upregulating PD-L1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 524.
Abstract 5243: CRISPR knockout: How to get high biallelic knockout
Authors: Li Yongqi , Min Li , Liu Ellen , Wang Yiran 
Published: August 2019

Abstract
Although homology directed repair (HDR)-mediated gene knockout / knockin is well established, it cannot necessarily be applied in some cell types and organisms with low HDR frequencies. Herein we describe an improved technology for genome-wide gene knockout / knockin using CRISPR-Cas9 targeted genome editing: CRISPR KN2.0. CRISPR KN2.0 technology is specifically designed to provide an easy-to-use and get around 50% biallelic knockout. This gene knockout / knockin technology is designed to knock out any DNA locus and knock in a functional cassette containing Green Fluorescence Protein (GFP) and puromycin resistant gene to facilitate screening process. Both of these cassettes are expressed under EF1A promoter after genomic integration. CRISPR KN 2.0 has been used to successfully knock out many genes / knocked in functional cassette in HeLa, HEK293T and MIA PaCa-2 (a human pancreatic carcinoma cell line) cells. Studies carried out in house and by some colleagues show that CRISPR KN 2.0 is highly efficient and render improved knockout/knockin rate (over 50% positively integrated colonies after puromycin selection).
Citation Format: Yongqi Li, Li Min, Ellen Liu, Yiran Wang. CRISPR knockout: How to get high biallelic knockout [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5243.