bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR03: Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for DNA methylation maintenance
Authors: Rothbart Scott B. , Dickson Bradley M. , Ong Michelle S. , Krajewski Krzysztof , Houliston Scott , Kireev Dmitri B. , Arrowsmith Cheryl H. , Strahl Brian D. 
Published: August 2014

Abstract
DNA methylation and histone post-translational modifications (PTMs) represent two key epigenetic regulators of DNA information in chromatin. The faithful inheritance of DNA methylation is essential for normal mammalian development and long-term transcriptional silencing, and aberrant DNA methylation patterns are a hallmark of many cancers. Histone PTMs can alter the physical structure of chromatin and have been proposed to function in the context of a “histone code” to coordinate the recruitment of effector proteins that elicit selective effects on chromatin-templated cellular processes like gene transcription and DNA repair. Indeed, defects in histone recognition by effector proteins are also emerging as underlying causes of cancer initiation and progression. Effector proteins often contain multiple chromatin binding domains. While significant progress has been made characterizing individual effector domains, the role of paired domains and how they function in a combinatorial fashion within chromatin is poorly defined. The E3 ubiquitin ligase UHRF1 is a unique chromatin effector protein, in that it integrates the recognition of both histone PTMs and DNA methylation. We recently showed that H3K9 methyl binding by the tandem Tudor domain (TTD) of UHRF1 is required for DNA methylation maintenance in cancer cells — yet the function of its adjacent plant homeodomain (PHD) in this process was unknown. Here we show that the linked TTD and PHD of UHRF1 operate as a single functional unit in cells, providing a defined combinatorial readout of the modification state of the histone H3 tail that is essential for UHRF1-directed DNA methylation maintenance by DNMT1. These findings provide critical support for the ‘histone code' hypothesis, demonstrating that multivalent histone engagement plays a fundamental role in driving a downstream biological event in chromatin and suggest UHRF1 may be a favorable therapeutic target for regulating aberrant DNA methylation in cancers.
This abstract is also presented as Poster B26.
Citation Format: Scott B. Rothbart, Bradley M. Dickson, Michelle S. Ong, Krzysztof Krajewski, Scott Houliston, Dmitri B. Kireev, Cheryl H. Arrowsmith, Brian D. Strahl. Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for DNA methylation maintenance. [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 PR03.
Abstract PR12: CHD5 is required for neurogenesis and has a dual role in facilitating gene expression and Polycomb gene repression
Authors: Egan Christopher M. , Nyman Ulrika , Skotte Julie , Streubel Gundula , Turner Siobhán , O'Connell David J. , Rraklli Vilma , Dolan Michael J. , Chadderton Naomi , Klaus Hansen , Jane Farrar Gwyneth , Helin Kristian , Holmberg Johan , Bracken Adrian P. 
Published: August 2014

Abstract
The chromatin remodeler CHD5 is expressed in neural tissues and is frequently deleted in aggressive neuroblastoma. Very little is known about the normal function of CHD5, its mechanism of action or how its deletion may contribute to neuroblastoma. Here we report that depletion of CHD5 in the developing murine neocortex blocks neuronal differentiation leading to an accumulation of undifferentiated progenitors. Consistent with this, ChIP-SEQ analysis of CHD5 shows it binds a large cohort of neuronal genes and is required for facilitating their activation during differentiation. However, CHD5 also binds a cohort of Polycomb target genes and is required for the maintenance of H3K27me3 on their promoters and their sustained repression during differentiation. Finally, we show that the chromodomains of CHD5 directly bind H3K27me3 and are essential for the function of CHD5 during neuronal differentiation. These findings provide new insights into the essential role of CHD5 during neurogenesis and show how the inactivation of this candidate tumor suppressor might contribute to the progression of neuroblastoma via a defect in differentiation.
This abstract is also presented as Poster A05.
Citation Format: Christopher M. Egan, Ulrika Nyman, Julie Skotte, Gundula Streubel, Siobhán Turner, David J. O'Connell, Vilma Rraklli, Michael J. Dolan, Naomi Chadderton, Hansen Klaus, Farrar Gwyneth Jane, Kristian Helin, Johan Holmberg, Adrian P. Bracken. CHD5 is required for neurogenesis and has a dual role in facilitating gene expression and Polycomb gene repression. [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 PR12.
Abstract PR16: A new class of small molecule acetyltransferase inhibitors discovered through high-throughput screening are potent anticancer agents with cancer-type specific activity
Authors: Yang Heng , Pinello Christie E. , Luo Jian , Li Dawei , Wang Yunfei , Lisa Zhao Y. , Jahn Stephan C. , Saldanha S. Adrian , Planck Jamie , Geary Kyla R. , Ma Haiching , Law Brian K. , Roush William R. , Hodder Peter , Liao Daiqing 
Published: August 2014

Abstract
Acetyltransferase p300 (KAT3B) plays key roles in signaling cascades that support cancer cell survival and sustained proliferation. p300 is overexpressed in several types of cancer, which correlates with tumor progression. Thus, p300 represents a rational anticancer therapeutic target. To discover novel anticancer agents that target p300, we conducted a high-throughput screening campaign. A library of 622,079 compounds was assayed for cytotoxicity to the triple-negative breast cancer (TNBC) cell line MDA-MB-231 but not to the human mammary epithelial cells. The resulting compounds were tested in a biochemical assay for inhibiting the enzymatic activity of p300. One compound (L002, NSC764414) displayed an IC50 of 1.98 μM against p300 in vitro, inhibited acetylation of histones and p53, and suppressed STAT3 activation in cell-based assays. L002 could be docked to the active site of the p300 catalytic domain. Biochemical tests of a series of related compounds revealed functional groups that may impact inhibitory potency of L002 against p300. Interestingly, these analogs showed inhibitory activities against CBP (the cellular paralog of p300), PCAF and GCN5, but not to other acetyltransferases (KAT5, KAT6B and KAT7), histone deacetylases (HDACs) and histone methyltransferases. Among the NCI-60 panel of cancer cell lines, leukemia and lymphoma cell lines were extremely sensitive to L002, whereas it is toxic to only a limited number of cell lines derived from solid tumors. Notably, breast cancer cell lines, especially those derived from TNBC, were highly susceptible to L002. In vivo, it potently suppressed tumor growth and histone acetylation of MDA-MB-468 xenografts. Thus, these new acetyltransferase inhibitors are potential anticancer therapeutics with specific activities against breast cancer and hematological malignancies.
This abstract is also presented as Poster B43.
Citation Format: Heng Yang, Christie E. Pinello, Jian Luo, Dawei Li, Yunfei Wang, Zhao Y. Lisa, Stephan C. Jahn, S. Adrian Saldanha, Jamie Planck, Kyla R. Geary, Haiching Ma, Brian K. Law, William R. Roush, Peter Hodder, Daiqing Liao. A new class of small molecule acetyltransferase inhibitors discovered through high-throughput screening are potent anticancer agents with cancer-type specific activity. [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 PR16.
Abstract A23: Novel ursolic acid derivatives with potent antitumor activity
Authors: Leal Ana S. , Salvador Jorge A.R. , Yongkui Jing 
Published: August 2014

Abstract
Cancer is the fourth leading cause of death worldwide, within pancreatic cancer is the fourth leading cause of cancer death and without effective medical therapy.1 Natural products provide a promising source for developing effective anticancer agents.2 Ursolic acid is a pentacyclic triterpenoid present in plants, vegetables, and fruits that has been found to have several biological activities, including antitumor activity.3 In order to improve the preexisting antitumor activity of ursolic acid, a panel of semisynthetic derivatives were prepared, characterized, and evaluated for the antiproliferative activities in several cancer cell lines.
Ursolic acid was chemically modified by the introduction of heterocyclic rings in several points of the backbone structure and was found that modifications at C2 had improved activities against proliferation of pancreatic cancer cell lines, inducing apoptosis with upregulation of p53 and NOXA levels, and downregulation of XIAP levels.
Fluor is a highly desirable atom, in key positions of active molecules can improve metabolic and chemical stability, membrane permeability and binding affinity.4 We have introduced fluor into the ring C of ursolic acid and a series of ursane-type fluor-derivatives were synthesized. The most potent derivative was 19-fold more active than ursolic acid to inhibit Aspc-1 cell growth and to arrest cell cycle at G1 phase with upregulation of p21waf1, and apoptosis at higher concentrations with upregulation of NOXA and downregulation of c-FLIP.
These new semisynthetic derivatives of ursolic acid may have potential for drug discovery to treat cancer.
Citation Format: Ana S. Leal, Jorge A.R. Salvador, Jing Yongkui. Novel ursolic acid derivatives with potent antitumor activity [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr A23.
Abstract A10: In silico design of biomarker-optimized drug combinations in ERBB2+ cancers
Authors: Du Jinyan , Kirouac Daniel , Lahdenranta Johanna , Overland Ryan , Onsum Matthew , McDonagh Charlotte 
Published: August 2014

Abstract
Crosstalk and compensatory circuits within cancer signaling networks fundamentally limit the activity of targeted therapies. Combination drug regimens are thus required to fully inhibit an oncogenic network. However, rationally designing optimal combinations, given the large number of targeted agents available remains a challenge. Previously, we developed a multi-scale systems model of ERBB2-high breast cancer to quantitatively interrogate relationships between biomarkers (proxies for the mode of network activation) and combination drug efficacy. We found that targeting the ERBB2-ERBB3 heterodimer with a combination of ERBB2 inhibitors (trastuzumab and lapatinib) and an ERBB3 inhibitor (MM-111) was more effective at inducing tumor regression than the combination of an AKT and MEK inhibitor (MK2206 and GSK1120212), and was significantly better tolerated. However, the model was parameterized based on data collected from one cell line. Here we have performed profiling of an 18-cell line panel to assess whether our model and results are extendable to other ERBB2-high cancers. We monitored cell viability and signaling events upon AKT and MEK inhibitor treatments in the presence or absence of the ERBB3 ligand heregulin in these cell lines. While all cells were ERBB2+, we observed widely variable phenotypic and signaling dependencies on the PI3K/AKT and MAPK/ERK pathway activities across the panel. At the phenotypic level, cells primarily depend on either AKT or ERK signaling in basal conditions. Interestingly, upon heregulin stimulation some cells lines switch pathway dependency from AKT to ERK. Adaptive feedback circuits downstream of ERK and AKT were identified in all cell lines, though the identity and strength vary extensively. ERBB3 signaling and total AKT were consistently up-regulated to various degrees upon AKT inhibitor treatment. In contrast, multiple ERBB receptors as well as other RTKS, AKT signaling, and total ERK were upregulated in the response to MEK inhibition. While it is plausible that signaling pathways beyond AKT and ERK are modulating cell viability, we are able to quantitatively describe cell growth regulation based on AKT and ERK pathway activity using quantitative logic-based modeling framework. Our results will help us better understand how signaling events are decoded by cancer cells into phenotypic responses, and enable in silico drug combination screening across molecularly and functionally heterogeneous cancers.
Citation Format: Jinyan Du, Daniel Kirouac, Johanna Lahdenranta, Ryan Overland, Matthew Onsum, Charlotte McDonagh. In silico design of biomarker-optimized drug combinations in ERBB2+ cancers. [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 A10.
Abstract A12: Combined EZH2 and PI3K inhibition as a novel therapy for treatment of castration resistant prostate cancer
Authors: Enos Miriam 
Published: August 2014

Abstract
Prostate cancer is the most frequently diagnosed non-dermatological malignancy in North American men. Presently, preventative testing and castration therapies are the only measures that effectively decrease mortality. However, these therapies are not effective in the case of the advanced disease, for which there is still no cure. As such, there is an unmet medical need to develop more effective therapies for castration-resistant, metastatic tumors.
Surprisingly, there are but a few things known about the signals that drive and maintain advanced disease. The PI3K/AKT signaling pathway is frequently deregulated in human malignancies and is activated in a majority of advanced stage carcinomas of the prostate. More recently, a member of PRC2 complex, EZH2, has been reported to be a marker and driver of late stage disease. Based on this knowledge about the key disregulated signaling pathways in prostate cancer, we decided to explore them as potential therapeutic avenues.
We found that both genetic and biochemical inhibition of EZH2 results in reduced proliferation and transformation in soft agar. Similarly, treating cells with a PI3K specific inhibitor, GDC- 0941 produces only a cytostatic effect, an observation that is supported by a body of literature suggesting that GDC-0941 is ineffective as a mono-therapy drug.
To this end we decided to explore the combination of both EZH2 and PI3K inhibitors and have found that simultaneous suppression of these two important oncogenic signals, kills androgen-dependent (AD) and independent (AI) prostate cancer cells in vitro and in vivo. Knock-down of another member of PRC2 complex, SUZ12, phenocopies this cytotoxicity when combined with PI3K inhibitor, suggesting that EZH2 role is PRC2-dependent.
These preliminary data suggest specific cooperation of EZH2 and PI3K/AKT signaling pathways in assuring cell survival and maintenance of tumorigenicity in prostate cancer cells. Currently we are exploring the potential downstream effectors that could be responsible for the synergy that we observe upon combination treatment.
Citation Format: Miriam Enos. Combined EZH2 and PI3K inhibition as a novel therapy for treatment of castration resistant 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 A12.
Abstract A18: CDK6 binds and promotes the degradation of the EYA2 protein
Authors: Kohrt Dawn , Crary Jennifer , Zimmer Marc , Ford Heide , Hinds Phi , Grossel Martha 
Published: August 2014

Abstract
Cyclin dependent kinase 6 (Cdk6) is a D-cyclin activated kinase that is directly involved in driving the cell cycle through inactivation of pRB in G1 phase. Increasingly, evidence suggests that CDK6, while directly driving the cell cycle, may only be essential for proliferation of specialized cell types, agreeing with the notion that CDK6 also plays an important role in differentiation. Here, evidence is presented that CDK6 binds to and promotes degradation of the EYA2 protein. The EYA proteins are a family of proteins that activate genes essential for the development of multiple organs, regulate cell proliferation, and are misregulated in several types of cancer. This interaction suggests that CDK6 regulates EYA2 activity, a mechanism that could be important in development and in cancer.
Citation Format: Dawn Kohrt, Jennifer Crary, Marc Zimmer, Heide Ford, Phi Hinds, Martha Grossel. CDK6 binds and promotes the degradation of the EYA2 protein. [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 A18.
Abstract A21: Direct transcriptional functions of the APC tumor suppressor in regulating gene expression
Authors: Hankey William , McIlhatton Michael A. , Lan Xun , Jegga Anil G. , Jin Victor X. , Aronow Bruce J. , Groden Joanna 
Published: August 2014

Abstract
Mutation of the APC tumor suppressor gene occurs in approximately 75% of colorectal cancers (CRC) and is considered the central event driving tumor initiation in the large intestine. The APC protein controls gene expression indirectly through the canonical WNT signaling pathway as a component of a cytoplasmic complex that promotes the proteolysis of the transcriptional co-regulator β-catenin. Recent studies have shown that APC is also a chromatin-associated protein that interacts with the promoter of the MYC proto-oncogene to downregulate its transcription. We have tested the hypothesis that APC similarly regulates other genes relevant to tumorigenesis, and that the 75% of CRCs that are deficient in APC may show abnormal activation or suppression of these genes, in comparison to the other 25% of CRCs. These differences could potentially underlie differences in tumor progression and/or responses to chemotherapy, and could enable the identification of new therapeutic targets.
The APC genotype of two CRC cell lines was manipulated using siRNA to reduce APC expression in one cell line wild-type for APC and using an APC transgene to induce exogenous APC expression in a second cell line mutated for APC. NanoString and RNA-seq technologies have generated gene expression datasets from these cell lines and identify more than 700 genes that could be directly regulated at the transcriptional level by APC. RT-PCR and in silico analyses have validated a smaller subset of these genes. Functional pathway analysis has led to the hypothesis that APC loss facilitates evasion of apoptosis, with a subset of 17 pro- and anti-apoptotic candidate genes implicated in this effect. Critical experiments in progress will confirm the extent to which the aberrant expression of these genes in vivo is specific to colon tumors lacking APC, using Apc-deficient and Apc-wild-type mouse models of intestinal cancer, and will identify direct chromatin binding sites of APC by ChIP-seq. These approaches will validate our gene expression analyses and identify a set of direct gene targets that APC regulates.
Citation Format: William Hankey, Michael A. McIlhatton, Xun Lan, Anil G. Jegga, Victor X. Jin, Bruce J. Aronow, Joanna Groden. Direct transcriptional functions of the APC tumor suppressor in regulating gene expression. [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 A21.
Abstract A22: Mechanisms of oncogenic cooperation between EGFR/Ras and Hippo pathways in Drosophila and human cellular transformation models
Authors: Hong Xin , Cohen Stephen Michael 
Published: August 2014

Abstract
The hippo/Salvador kinase cascade is a highly conserved signaling pathway regulating growth and organ size from Drosophila to mammals. The invertebrate-specific microRNA, bantam, is a key target and effector downstream of the Drosophila hippo pathway. Bantam inhibits the pro-apoptotic factor hid and promotes growth through an as yet unidentified mechanism. The EGFR/Ras pathway coordinates growth and patterning in Drosophila. We characterize a molecular circuit involving bantam, socs36E and EGFR that regulates tissue growth. Socs36E is a direct bantam target that negatively regulates wing size. Socs36E buffers EGFR activity by acting in a negative feedback loop with EGFR. Interestingly, bantam and socs36E repress each other forming a potential bistable switch. This switch might allow effective repression of socs36E during the rapid growth phase of wing disc development. Therefore, bantam represents a unique molecular linkage connecting hippo and EGFR signaling in promoting growth. Furthermore, we found that the mammalian socs family members SOCS5 and SOCS6 are targeted by an oncogenic miRNA, which plays a role in RasV12 mediated tumoriogenesis in soft agar assays. Therefore, the SOCS family proteins are evolutionarily conserved regulators of growth and cancer transformation.
Citation Format: Xin Hong, Stephen Michael Cohen. Mechanisms of oncogenic cooperation between EGFR/Ras and Hippo pathways in Drosophila and human cellular transformation models. [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 A22.