bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1371: Isoprenylcysteine carboxylmethyltransferase (ICMT) function is critical for epithelial malignant transformation by mutant-Ras
Authors: Lau Hiu Yeung , Tang Jingyi , Casey Patrick J. , Wang Mei 
Published: July 2017

Abstract
Purpose Limited progress has been made in the development of direct inhibitors of Ras. Therefore, targeting isoprenylcysteine carboxylmethyltransferase (ICMT), the final enzyme in the prenylation pathway for Ras and other proteins containing the so-called CaaX-motif, remains an important strategy to inhibit Ras function in cancers. In this study, we investigate the role ICMT plays in the initiation of human epithelial cancers involving constitutively-active mutant Ras using genetic manipulation strategies.
Methods Small T antigen and a shRNA against p53 (shp53) were sequentially expressed in human mammary epithelial cells immortalized by hTERT (HME1-hTERT) to create pre-malignant HME1-shp53 cells. All 4 isoforms of wild-type or mutant Ras, namely H-Ras, N-Ras, K-Ras-4A and K-Ras-4B, were independently introduced into HME1-shp53 cells to determine their transforming ability. Using CRISPR-Cas9 genome editing technology, ICMT-null HME1-shp53 cells were generated and mutant Ras isoforms were subsequently introduced; tumor formation abilities of thus generated cells were determined using soft-agar anchorage-independent colony formation assay and subcutaneous xenografts in mice. ICMT knock-out was also performed in MiaPaCa-2 and MDA-MB-231 cells, both expressing mutant K-Ras, and subcutaneous xenograft tumor formation in mice was measured.
Results Pre-malignant HME1-shp53 cells can be transformed by all mutant Ras isoforms but not by any wild-type Ras. ICMT loss-of-function dramatically reduced anchorage-independent colony formation caused by all mutant Ras isoforms in HME1-shp53 cells, and in vivo xenograft formation was completely abolished. ICMT loss-of-function also dramatically reduced in vivo xenograft formation for mutant K-Ras-expressing MiaPaCa-2 and MDA-MB-231 naturally-occurring cancer cells.
Conclusion ICMT function is essential for the malignant transformation of HME1 cells by all isoforms of Ras. Furthermore, ICMT function is also crucial for the maintenance of the malignant phenotype in mutant K-Ras-expresing cells such as MiaPaCa-2 and MDA-MB-231 cells.
Citation Format: Hiu Yeung Lau, Jingyi Tang, Patrick J. Casey, Mei Wang. Isoprenylcysteine carboxylmethyltransferase (ICMT) function is critical for epithelial malignant transformation by mutant-Ras [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 1371. doi:10.1158/1538-7445.AM2017-1371
Abstract 1373: The role of the ASH1L SET domain in leukemogenesis
Authors: Rogawski David , Miao Hongzhi , Kempinska Katarzyna , Chen Lili , Chase Jen , Friedman Ann , Yan Xiaomei , Nishioka Kenichi , Huang Gang , Ernst Patricia , Muntean Andy , Maillard Ivan , Cierpicki Tomasz , Grembecka Jolanta 
Published: July 2017

Abstract
ASH1L (absent, small, or homeotic-like 1) is a histone lysine methyltransferase (KMTase) specific for histone 3, lysine 36 that has an emerging role in multiple types of cancer. During development, ASH1L activates HOX genes and regulates self-renewal potential of long-term hematopoietic stem cells. Interestingly, HOX genes are oncogenic drivers in a variety of cancer types. For example, overexpression of HOXA9 is highly associated with a poor prognosis in acute myeloid leukemia (AML). In addition, ASH1L is overexpressed in a variety of cancers, including breast and thyroid cancer, but its role in cancer remains poorly characterized. Recent data suggest that ASH1L promotes leukemogenesis in mixed-lineage leukemia by recruiting the MLL epigenetic regulator to target genes. However, ASH1L is a large protein with multiple chromatin-interacting domains, and which regions of the ASH1L protein are important in leukemia has not been reported. Specifically, the role of ASH1L’s KMTase activity in leukemogenesis remains unknown.
To further investigate the function of ASH1L in leukemia, we knocked down expression of ASH1L in leukemia cell lines. We found that ASH1L knockdown slowed cell growth and caused a decrease in expression of HOXA genes and their collaborator MEIS1. To specifically investigate the role of ASH1L KMTase activity in leukemia, we used a mouse model with a targeted in-frame deletion of the ASH1L SET domain (ΔSET). ΔSET cells express a shorter version of ASH1L that does not contain the SET domain. We transduced bone marrow cells (BMCs) isolated from ΔSET and WT mice with several oncogenes relevant to AML to determine the role of the ASH1L SET domain in leukemic transformation. We found that ΔSET BMCs were significantly impaired in leukemic transformation compared to WT BMCs, as manifested by decreased colony-forming ability and reduced expression of HOXA genes. These findings suggest that the ASH1L SET domain plays an important role in leukemogenesis mediated by multiple different oncogenes. Future studies will further characterize ASH1L’s role in leukemia by identifying the complete set of genetic loci that it methylates and regulates, and will determine whether the ASH1L SET domain represents a viable therapeutic target.
Citation Format: David Rogawski, Hongzhi Miao, Katarzyna Kempinska, Lili Chen, Jen Chase, Ann Friedman, Xiaomei Yan, Kenichi Nishioka, Gang Huang, Patricia Ernst, Andy Muntean, Ivan Maillard, Tomasz Cierpicki, Jolanta Grembecka. The role of the ASH1L SET domain in leukemogenesis [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 1373. doi:10.1158/1538-7445.AM2017-1373
Abstract 1375: Loss of C-MYC and chromatin acetylation induce epigenetic reprogramming in acute lymphoblastic leukemia
Authors: Costa Elodie M. Da , Armaos Gregory , Jacques-Ricard Simon , Beaudry Annie , St-Onge Pascal , Caron Maxime , Sinnett Daniel , McGraw Serge , Raynal Noël J. 
Published: July 2017

Abstract
Epigenetic modifications play a key role in establishing and maintaining gene expression. In cancer, they are highly altered and responsable of gene expression deregulation. Epigenetic drugs have the ability to reset cancer cell epigenome producing cancer cell differentiation and apoptosis. In a drug screening initiative, we recently reported a series of FDA-approved drugs with unsuspected epigenetic and anticancer activities. Here, we tested in a secondary screen the activity of these drugs against acute lymphoblastic leukemia (ALL) cell lines (MOLT-4 and NALM-6). We found that Proscillaridin A, a cardiac glycoside used for heart failure treatment, was the most active with IC50 values in the low nanomolar range, suggesting drug repositioning potential. Proscillaridin treatments induced a significant decrease in RNA and protein levels of C-MYC, a master oncogenic driver in ALL. Shortly after proscillaridin A treatment, C-MYC exhibited a 75% reduction in lysine acetylation, a post-translational modification known to prevent its degradation. Loss of acetylation was associated with down-regulation of lysine acetyltransferases CBP, P300 and Tip60, which also correlated with a reduction in histone 3 and 4 acetylation levels (H3K14ac, H3K9ac, H3K27ac and H4K5ac). Preliminary analysis with si-RNA experiments reveal that independent HAT activities are not responsible of C-MYC downregulation. RNA sequencing and gene set enrichment analysis in proscillaridin-treated ALL cells (5 nM for 48h) showed that genes associated with cell differentiation and apoptosis pathways were up-regulated whereas down-regulated genes were associated with C-MYC target genes. Altogether, our findings show that acetylation through lysine acetyltransferase down-regulation simultaneously induces loss of C-MYC and H3 acetylation leading to epigenetic reprogramming in ALL cells. This drug repositioning strategy, using proscillaridin A, has the potential to reprogram cancer cells that are driven by MYC overexpression or hyperactivation.
Citation Format: Elodie M. Da Costa, Gregory Armaos, Simon Jacques-Ricard, Annie Beaudry, Pascal St-Onge, Maxime Caron, Daniel Sinnett, Serge McGraw, Noël J. Raynal. Loss of C-MYC and chromatin acetylation induce epigenetic reprogramming in acute lymphoblastic leukemia [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 1375. doi:10.1158/1538-7445.AM2017-1375
Abstract 1377: Set7 is a novel histone methyltransferase in Schizosaccharomyces Pombe
Authors: Luccio Eric Di , Shen Yunpeng , Mevius Damiaan E.H.F , Noh Yeon Jeong , Kim Jihyeon , Morishita Masayo 
Published: July 2017

Abstract
Dynamics and plasticity of chromatin regulation is mediated by a molecular ballet of writers, readers and erasers of epigenetic marks on both DNA and histones. The pattern of histone modifications may define a histone code, which is part of intricate networks that ultimately regulate transcriptional events. Dysfunction of histone methylation affects chromatin regulation and is involved in an increasing number of pathologies from cellular transformation to tumor progression and other diseases. However, histone methyltransferase (HMTase) pathways remain to be further explored and better understood.
Fission yeast (Schizosaccharomyces pombe) is an ideal model organism to investigate the fundamental mechanisms of chromatin dynamics. Fission yeast possesses 13 SET-containing proteins (Set1 to 13), several of which methylate histones or ribosomes. The catalytic SET domain is highly conserved across eukaryotes (e.g. Set2, a homologue of the oncoprotein NSD2/MMSET/WHSC1 in human). Structure-function studies of HMTases are essential from basic science to translational research. However, full-length structures of fission yeast methyltransferases are still scarce.
Here, in a bid to better understand histone methylation and to gain insight for drug-design, we report the identification and structural characterization of a novel histone methyltransferase Set7 (SPCC297.04c), in Schizosaccharomyces Pombe. In this study, we investigated Sp.Set7’s cellular localization and the effect of Sp.Set7 knock-out on the cell cycle and sporulation. Next, we elucidated Sp.Set7’s Lysine substrate specificity on histone H3 and H4 by biochemical assays and mass spectrometry. Finally, we solved the X-ray structure of the apo Sp.Set7 at 2.0 Å resolution.
In summary, we report the biochemical and structural characterization of a novel histone methyltransferase in fission yeast, which has implications for better understanding the fundamental mechanism of HMTases.
Citation Format: Eric Di Luccio, Yunpeng Shen, Damiaan E.H.F Mevius, Yeon Jeong Noh, Jihyeon Kim, Masayo Morishita. Set7 is a novel histone methyltransferase in Schizosaccharomyces Pombe [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 1377. doi:10.1158/1538-7445.AM2017-1377
Abstract 1381: Human CRL4DDB2 E3 ubiquitin ligase regulates post-repair chromatin restoration of epigenetic marker H3K56Ac through recruitment of histone chaperon CAF-1
Authors: Zhu Qianzheng , Sharma Nidhi , He Jinshan , Wani Gulzar , Wani Altaf A. 
Published: July 2017

Abstract
Epigenetic marker acetylated histone H3 lysine 56 (H3K56Ac) diminishes as an early DNA damage response but is restored in chromatin after DNA repair. Here, we report that human CRL4DDB2 ubiquitin ligase regulates the DNA repair-driven chromatin restoration of H3K56Ac by monitoring the recruitment of histone chaperon CAF-1. We show that the H3K56Ac accumulates at DNA damage sites. The post-repair H3K56Ac restoration depends on CAF-1 and CBP/p300 function. The CRL4DDB2 components DDB1, DDB2 and CUL4A are required not only for maintaining the H3K56Ac level in chromatin, but also for restoring H3K56Ac following the repair of DNA photolesions and strand breaks. Depletion of CUL4A decreases the recruitment of CAF-1 p60 and p150 to ultraviolet radiation (UVR)- and phleomycin-induced DNA damage. Inhibition of neddylation renders CRL4DDB2 inactive and concomitantly diminishes the recruitment of CAF-1 and prevents post-repair H3K56Ac restoration. Additionally, a PCNA-interacting protein (PIP) motif is shown to exist within DDB2. The mutation in the PIP box of DDB2 compromises its capability to maintain the H3K56Ac level but does not affect CRL4DDB2-mediated XPC ubiquitination. These results suggest a novel role of CRL4DDB2 in regulating post-repair chromatin restoration, which differs from its canonical role in the process of nucleotide excision repair.
Citation Format: Qianzheng Zhu, Nidhi Sharma, Jinshan He, Gulzar Wani, Altaf A. Wani. Human CRL4DDB2 E3 ubiquitin ligase regulates post-repair chromatin restoration of epigenetic marker H3K56Ac through recruitment of histone chaperon CAF-1 [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 1381. doi:10.1158/1538-7445.AM2017-1381
Abstract 1386: Effects of histone deacetylase inhibitors on differentiation markers and growth of colon and bladder cancer cells
Authors: Lea Michael A. , Cué Lauren , Batista Elizabeth , Lew Erik , desBordes Charles 
Published: July 2017

Abstract
Alkaline phosphatase and dipeptidyl peptidase are markers of differentiation in colon cancer cells. In colon cancer cells differentiation can often be induced by treatment with inhibitors of histone deacetylase (HDAC) activity. In some colon cancer cells butyrate causes a several-fold induction of alkaline phosphatase but only modest effects on dipeptidyl peptidase. There is relatively little information on changes in activity of cell surface hydrolases in bladder cancer. However, there is some evidence for decreased alkaline phosphatase activity in bladder cancer. We tested the hypothesis that there may be retention of activity in more slowly growing cancer cells and the activity will be regulated by HDAC inhibitors in a manner similar to that in colon cancer. In our initial studies we screened seven human bladder cancer cell lines for alkaline phosphatase activity. We identified three cell lines (5637, HT1197 and HT1376) with activity comparable to that in more differentiated colon cancer cell lines. The response to incubation with the HDAC inhibitors butyrate and valproate was compared with effects in three colon cancer cell lines Caco-2, HT29 and SW1116. In all six cell lines there were growth inhibitory effects that tended to be a little greater with butyrate than with valproate. Induction of alkaline phosphatase activity was generally greater with butyrate than with valproate and was apparent even without normalizing the activity on a protein basis. After determining the activity per unit protein there were increases in dipeptidyl peptidase activity after treatment with the HDAC inhibitors that were smaller than for alkaline phosphatase. Growth inhibition was observed with all the HDAC inhibitors examined including LMK235, nicotinamide, RGFP966, romidepsin and tubacin but increased activity of alkaline phosphatase was not always seen. Activities of the enzymes were very low in CRL1790 human colonocytes of fetal origin and there was little or no induction with HDAC inhibitors. Although pyruvate and carnitine have been reported to be HDAC inhibitors, incubation with colon and bladder cancer cells did not cause induction of alkaline phosphatase activity. It was concluded that regulation of alkaline phosphatase and dipeptidyl peptidase by HDAC inhibitors can be similar in bladder and colon cancer cells.
Citation Format: Michael A. Lea, Lauren Cué, Elizabeth Batista, Erik Lew, Charles desBordes. Effects of histone deacetylase inhibitors on differentiation markers and growth of colon and bladder cancer 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 1386. doi:10.1158/1538-7445.AM2017-1386
Abstract 1401: Deterring breast cancer progression. The critical role of a lipid-sphingolipid epigenetic mechanism of cell fate
Authors: Rossetti Stefano , Gagliostro Vincenzo , Sacchi Nicoletta 
Published: July 2017

Abstract
Genetic and environmental factors cooperate to assure precise genome-wide epigenetic regulation of the mammary epithelia cell transcriptome. Our interest in regulatory epigenetic mechanisms that, by determining mammary epithelial cell decisions, are pivotal to deter the onset and progression of breast cancer, let us identify a regulatory epigenetic mechanism of mammary morphogenesis that links a physiological regulatory lipid of environmental origin (all-trans retinoic acid, RA) with sphingolipids capable of determining either cell death (ceramide, CER) or cell life (sphingosine 1 phosphate, S1P).
Whenever RA, for different reasons, fails to perform the epigenetic transcriptional control of neutral sphingomyelinase 2 (nSMase2/SMDP3), involved in the synthesis of pro-apoptotic CER, S1P fosters both pro-proliferative and pro-invasive activity. Apparently, in the absence of epigenetic control of CER production by RA, S1P contributes to determine RA tumorigenic action. This study provides the rationale for combination therapeutic approaches with epigenetic drugs and inhibitors of either sphingosine kinase, the enzyme involved in S1P synthesis, or S1P receptors.
This study was supported by the NCI R01 CA127614 grant (NS).
Citation Format: Stefano Rossetti, Vincenzo Gagliostro, Nicoletta Sacchi. Deterring breast cancer progression. The critical role of a lipid-sphingolipid epigenetic mechanism of cell fate [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 1401. doi:10.1158/1538-7445.AM2017-1401
Abstract 1412: High EGFR somatic mutation frequency targeting the TK domain in colorectal cancer patients with microsatellite instability (MSI)
Authors: Deihimi Safoora , Slifker Michael , Ross Eric A. , El-Deiry Wafik S. 
Published: July 2017

Abstract
CRCs arise through genetic changes that impact various driver genes and in some tumors increased mutation rate in microsatellite unstable tumors. The hypermutable phenotype associated with microsatellite instability (MSI) results from loss of the mismatch repair system (MMR) activity. MSI is detected in 15% of all CRCs, and such tumors have a better prognosis and different chemotherapeutic outcome patterns, including high clinical benefit from immune checkpoint therapy or relative resistance to 5-FU as compared to microsatellite stable (MSS) tumors. The epidermal growth factor receptor (EGFR) signaling pathway plays an essential role in carcinogenesis of CRCs and is known to be overexpressed in MSI CRCs while highly mutated in Lung cancer. We analyzed the mutation frequency of deregulated pathways including EGFR and its downstream genes KRAS and BRAF in CRCs. We found a significantly elevated EGFR mutation frequency in CRC MSI-H subtype (45.5% vs. 6.5% in MSS CRCs, p&lt;0.0000001). Although KRAS and NRAS are mutated with high frequency in both MSI-H and MSS groups, BRAF corresponding to RTK-RAS pathways is more altered in MSI-H than MSS CRCs (32.67% vs 13.10%; p=0.001), consistent with the known association between MSI-H CRCs and BRAF mutations. We hypothesized that there might be a mutation pattern in EGFR in CRC subtypes that provide a rationale for EGFR-targeted therapy for a subtype of CRC. Of 1104 profiled CRCs in the COSMIC v73 database, somatic EGFR mutations were mapped for 101 MSI-High versus 916 MSS CRCs. EGFR mutations mapped on the protein structure revealed that mutations are mainly targeting tyrosine kinase (TK) domain while the extracellular domain remained mostly wild-type with potential for targeting by anti-EGFR monoclonal antibodies. It is known that downstream genes such as KRAS as well as expression levels of EGFR ligands can affect the sensitivity of CRCs to anti-EGFR therapy. We didn’t detect any difference in mRNA expression level between MSI-H and MSS group but our analysis is indicative of the presence of G12D mutations in a high proportion of KRAS-mutated MSS CRCs, therefore resistance to anti-EGFR antibodies such as cetuximab would be expected. However, EGFR tyrosine kinase inhibitors such as erlotinib and gefitinib could be considered for further testing in patients with MSI-H tumors that have a lower frequency of G12D KRAS mutations and may have mutant EGFR.
Citation Format: Safoora Deihimi, Michael Slifker, Eric A. Ross, Wafik S. El-Deiry. High EGFR somatic mutation frequency targeting the TK domain in colorectal cancer patients with microsatellite instability (MSI) [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 1412. doi:10.1158/1538-7445.AM2017-1412
Abstract 1423: Nedd8-activating enzyme inhibitor pevonedistat synergizes with cisplatin and carboplatin through interference with nucleotide excision repair and interstrand cross-link repair mechanisms in non-small cell lung cancer
Authors: Liu Xiaozhen , Bouck David , Garcia Khristofer , Blank Jonathan , Bernard Hugues , Berger Allison , Kuranda Mike , Koenig Erik , Lightcap Eric 
Published: July 2017

Abstract
Platins are one of the most widely used classes of chemotherapeutic drugs. Although used as part of first-line standard of care regimens for advanced non-small cell lung cancer (NSCLC), their effectiveness remains limited, with a 5-year survival rate of 18%. Therefore, combination therapy to overcome resistance and improve survival is needed. Pevonedistat (TAK-924/MLN4924) is an investigational first-in-class Nedd8-activating enzyme (NAE) inhibitor that blocks activation of the cullin family of E3 ubiquitin ligases by preventing cullin conjugation with Nedd8, a ubiquitin-like protein. In vitro, pevonedistat is synergistic with carboplatin in a cell viability assay in 6 out of 20 NSCLC cell lines either with or without paclitaxel. In vivo studies using patient-derived xenograft (PDX) models showed a combination effect in a carboplatin-insensitive but not carboplatin-sensitive model. To evaluate the mechanism of the synergy between pevonedistat and platinum, RNAi of 320 DNA-damage response genes was performed in 4 cell lines in vitro. Depletion of genes involved in TC-NER (transcription-coupled nucleotide excision repair) and ICR (interstrand crosslink repair) reduced the synergy between pevonedistat and platinum, with the contribution of each pathway varying by cell line. Since TC-NER and ICR are also involved in the repair of DNA damage by platins, the results suggest that delaying completion of platin induced DNA repair by pevonedistat results in enhanced cell death. Pevonedistat may impede TC-NER by inhibition of neddylation of the E3 ubiquitin ligase CUL4-RBX1-DDB1-ERCC8, thereby possibly providing a direct reversal of resistance to platins.
Citation Format: Xiaozhen Liu, David Bouck, Khristofer Garcia, Jonathan Blank, Hugues Bernard, Allison Berger, Mike Kuranda, Erik Koenig, Eric Lightcap. Nedd8-activating enzyme inhibitor pevonedistat synergizes with cisplatin and carboplatin through interference with nucleotide excision repair and interstrand cross-link repair mechanisms in non-small cell lung 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 1423. doi:10.1158/1538-7445.AM2017-1423