bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2493: Inactivation of ARID1A-SWI/SNF complex alters chromatin compactness at enhancer regions and affects transcription of key tumor signaling circuitry
Authors: Rahmanto Yohan Suryo , Shi Xu , Shen Wenjing , Miyamoto Tsutomu , Yu Yu , Chen Xi , Lee Meng-Horng , Singh Vivek , Vitolo Michele I. , Wirtz Denis , Drapkin Ronny , Xuan Jianhua , Shih Ie-Ming , Wang Tian-Li 
Published: August 2018

Abstract
Somatic mutations in ARID1A, a SWI/SNF chromatin remodeling gene, are prevalent in human cancer and represent an emerging mechanism by which a molecular genetic alteration reprograms epigenomes and propels tumorigenesis. Through comprehensive sequencing of chromatin immunoprecipitation and chromatin accessibility, we found chromatin binding regions for ARID1A/BRG1-containing SWI/SNF remodeling complexes, which were enriched at enhancers and corresponded to euchromatin state. ARID1A deletion caused global re-distribution of BRG1-containing complexes in chromatin. Integrative analyses of ATAC-seq, ChIP-seq, and transcriptome data obtained from endometrial epithelium and human endometrioid carcinomas identified high-confidence ARID1A-regulated genes that participate in myriad key tumor and developmental signaling circuitry tissue. Deletion of Arid1a was found to inactivate the TGF-β pathway and to accelerate tumor progression from pre-cancerous lesions to endometrioid carcinomas. This study provides compelling evidence that Arid1a loss is required for developing endometrial cancer from its precursor. Collectively, targeting epigenomic modifications may hold promise for suppressing invasive behaviors of neoplasms carrying ARID1A mutations.
Citation Format: Yohan Suryo Rahmanto, Xu Shi, Wenjing Shen, Tsutomu Miyamoto, Yu Yu, Xi Chen, Meng-Horng Lee, Vivek Singh, Michele I. Vitolo, Denis Wirtz, Ronny Drapkin, Jianhua Xuan, Ie-Ming Shih, Tian-Li Wang. Inactivation of ARID1A-SWI/SNF complex alters chromatin compactness at enhancer regions and affects transcription of key tumor signaling circuitry [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 2493.
Abstract 2499: Identification of functional proteins interacting with NSD2 in multiple myeloma
Authors: Chooi Jing Yuan , Xie Zhigang , Swa Hannah Lee-Foon , Gunaratne Jayantha , Kappei Dennis , Chng Wee Joo 
Published: August 2018

Abstract
Multiple myeloma (MM), characterized by the uncontrolled proliferation of malignant plasma cells, occurs mainly in the elderly population. Recurrent chromosomal translocations are central to the pathogenesis of MM, with t(4;14) being the second most common and associated with poor prognosis. The histone methyltransferase (HMTase) NSD2 is overexpressed in MM due to the t(4;14) translocation and has been suggested to play an important tumorigenic role in t(4;14) MM. However, the detailed molecular mechanism or signaling pathways describing how deregulation of NDS2 contributes to MM cell growth and survival are still uncertain. In this study, stable isotope labeling of amino acid in cell culture (SILAC)-based mass spectrometry analysis was used to determine NSD2-interacting proteins. Mass spectrometry analysis indicated that there were 75 proteins identified in the immunoprecipitation of NSD2 protein complexes. Gene ontology (GO) enrichment analysis showed that these proteins were enriched in processes related to chromatin organization, RNA processing and translation. Five high potential MMSET-interacting proteins from the most enriched functions were selected and verified by Immunoprecipitation and Western blot assays. The results indicated that there were interactions between NSD2 and SMARCA2, topoisomerase IIa, ADAR1, DDX5 and RPS6. In silico analysis with STRING database showed that SMARCA2 interacts with NSD2. SMARCA2 is the ATPase subunit of the SWI/SNF chromatin remodeling complex, which harnesses the energy from ATP to remodel the position of nucleosomes, making the DNA accessible during transcription, replication and DNA repair. Double immunofluorescence showed NSD2 and SMARCA2 co-localized in the cell nucleus. SMARCA2 was knocked down (KD) by shRNAs in t(4;14) MM cells. CellTiter-Glo Luminescent Cell Viability Assay (CTG assay) indicated that SMARCA2 KD by shRNA reduced t(4;14) MM cell growth. SMARCA2 KD also significantly inhibited the capacity to form colonies in t(4;14) MM cells on methylcellulose colony formation assay. Inhibiting SMARCA2 with active DNA-dependent ATPase A domain inhibitor (ADAADi) also reduced t(4;14) MM cell growth. In addition, SMARCA2 KD reduced cell cycle S phase. Western blot analysis showed downregulation of PRL3 and CCND1 protein level upon NSD2 or SMARCA2 KD. This study reveals a protein-protein interaction between NSD2 and SMARCA2. SMARCA2 KD showed SMARCA2 might be a novel therapeutic target for t(4;14) MM.
Citation Format: Jing Yuan Chooi, Zhigang Xie, Hannah Lee-Foon Swa, Jayantha Gunaratne, Dennis Kappei, Wee Joo Chng. Identification of functional proteins interacting with NSD2 in multiple myeloma [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 2499.
Abstract 2517: The role of endocytic traffic regulator EHD1 in EGFR traffic and breast cancer
Authors: Mushtaq Insha , Tom Eric C. , Arya Priyanka , Bielecki Timothy , Mohapatra Bhopal , Mirza Sameer , Storck Matthew D. , Ahmad Dena , Ansari Rokaya El , Rakha Emad , Band Vimla , Band Hamid 
Published: August 2018

Abstract
Epidermal growth factor receptor (EGFR) is a prototype receptor tyrosine kinase and serves as an oncogene in a variety of solid tumors. Its surface expression is dynamically regulated, and display of an activation-competent cell surface pool is an essential pre-requisite for cellular responses to EGF and other ligands, as well as for its oncogenic function. While mechanisms that regulate the post-activation endocytic fate of EGFR have received much attention, little is known about the mechanisms that control the basal, pre-activation, surface display of EGFR. Here, we identify a novel role of the endocytic recycling regulator EHD1 in the cell surface display of EGFR and EGF-driven functional responses. We demonstrate that inducible knockdown of EHD1 in human mammary epithelial cells impairs the EGFR delivery to the cell surface, resulting in reduced EGFR cell surface expression and accumulation in the Golgi, a phenotype rescued by exogenous EHD1. Reduced surface display of EGFR by depletion of EHD1 impaired EGF-induced proliferation mammary epithelial cells and a breast cancer cell line, demonstrating that the new molecular pathway we describe is functionally important. Given the role of EGFR and its family members in breast cancer, we carried out IHC screening of EHD1 expression in human breast cancer using tissue microarrays from a large (&gt;800 samples) and well-annotated breast cancer cohort. Of the 757 evaluable samples, EHD1 was overexpressed in 115 (15%) patients. Notably, a substantially higher percentage of HER2/ErbB2+ patients (25%) showed EHD1 overexpression. Survival analysis revealed that EHD1 overexpression was associated with a significantly shorter overall survival over 15 years of follow up. These studies reveal novel roles of EHD1 in regulating EGFR traffic and suggest its potential roles in regulating other EGFR family members, especially HER2/ErbB2. Our patient sample analyses support a role for EHD1 overexpression in promoting breast tumorigenesis. Future studies will be directed at directly testing the role of EHD1, and its family members, in HER2 traffic and the role of EHD1 in breast tumorigenesis. As EHD proteins possess ATPase activity, which is required for their function, our studies raise the prospect of developing inhibitors of these enzymes as potential anti-cancer agents.
Citation Format: Insha Mushtaq, Eric C. Tom, Priyanka Arya, Timothy Bielecki, Bhopal Mohapatra, Sameer Mirza, Matthew D. Storck, Dena Ahmad, Rokaya El Ansari, Emad Rakha, Vimla Band, Hamid Band. The role of endocytic traffic regulator EHD1 in EGFR traffic and breast cancer [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 2517.
Abstract 2520: FGFR2 and miR-671-5p as key participants involved in the progression of human esophageal squamous cell carcinoma
Authors: Chen Xiaojia , Li Xiaoyan , Tian Baoqing , Tan Xuan , Han Wei , Wang Jiakang , Hong An 
Published: August 2018

Abstract
Esophageal cancer is the world's tenth common malignant tumor. Esophageal cancer is divided into esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (ECA). ESCC is the dominant histological subtype. The overall 5-year survival rate for people with advanced-stage of ESCC is only about 10%-20%, but ESCC is still not well-studied. Therefore, it is very important to study the mechanism of cancer progression in ESCC in order to develop new therapies for this deadly disease.
Fibroblast growth factor receptor2 (FGFR2) is one of the RTK members and generally regarded as an oncogene, but little is known about its function in ESCC. In our study, we proved FGFR2 played the key role in ESCC progression. From In vitro studies, overexpression of FGFR2 promoted the ESCC cells' migration, invasion, and proliferation, which was confirmed through knocking down FGFR2 in ESCC cells. In vivo xenograft tumor mouse model studies showed the tumor size from ESCC cells with FGFR2 over-expression larger than that of the control group. Conversely, the tumor size from ESCC cells with FGFR2 knock-down was significantly smaller compared with the control group. Molecular mechanism studies showed that overexpression of FGFR2 activated the ERK and AKT signal pathways and altered the cell cycle in ESCC.
In addition, decreased expression of miR-671-5p was identified by microRNA array and QPCR verify assay in ESCC–FGFR2+ tissue. Using a dual influence report system, we confirmed miR-671-5p could regulate expression of FGFR2. It was also found that FGFR2 was highly expressed whereas miR-671-5p was expressed at a low level in most of the FGFR2-positive ESCC clinic samples. Furthermore, we demonstrated that miR-671-5p could inhibit the proliferation and metastasis of ESCC cells in vitro and it could suppress growth of ESCC in vivo. The miR-671-5p suppressed MAPK and PI3K signal pathways through down-regulation of phosphorylation of FGFR2. Therefore, miR-671-5p was seen as a tumor suppressor in ESCC.
Our results demonstrated that FGFR2 and miR-671-5p are potential therapeutic targets in ESCC. They both participate in the progression of ESCC, but also play the contrasting roles. Antagonists of FGFR2 or activators of miR-671-5p could be therapeutics against ESCC.
Citation Format: Xiaojia Chen, Xiaoyan Li, Baoqing Tian, Xuan Tan, Wei Han, Jiakang Wang, An Hong. FGFR2 and miR-671-5p as key participants involved in the progression of human esophageal squamous cell carcinoma [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 2520.
Abstract 253: Gnetin C as a candidate for targeted chemopreventive and therapeutic measures in prostate cancer
Authors: Kolhatkar Urvi , Dholakia Kshiti , Sikorska Gabriela , Kumar Avinash , Martinez Luis A. , Levenson Anait S. 
Published: August 2018

Abstract
Overexpression of chromatin modifier protein, metastasis-associated protein 1 (MTA1) in prostate cancer contributes to tumor aggressiveness and metastasis. MTA1 ChiP-Seq analysis identified downstream targets that are transcriptionally regulated by MTA1 and suggested a link between MTA1 and ETS2. The effects of ETS2 in cancer are context-dependent and both oncogenic and tumor suppressive functions have been described. We have shown that there is a positive correlation between MTA1 and ETS2 using loss of function studies and various preclinical models of prostate cancer. Our conclusion that MTA1 functions as a co-activator for regulating ETS2 expression in prostate cancer leading to promotion of prostate cancer progression, prompted us to look for pharmacological inhibitors of MTA1/ETS2 axis. In our previous studies, we reported inhibition of MTA1 by resveratrol and its potent analog pterostilbene in vitro and in vivo. We have demonstrated that pterostilbene treatment blocks the progression of PIN and adenocarcinoma in xenografts and transgenic mouse models by inhibiting MTA1 expression and signaling. Here, we found that Gnetin C, double-resveratrol, has more potent inhibition of MTA1/ETS2 axis than other stilbenes. Gnetin C, a resveratrol dimer, is found abundantly in melinjo plant widely cultivated in Southeast Asia; its seeds and fruits are common ingredients in Indonesian culinary. As resveratrol and pterostilbene, Gnetin C has been reported to possess anti-inflammatory and anticancer activity, however it has not been considered as chemopreventive agent in prostate cancer. Using two prostate cancer cell lines, namely DU145 and PC3M cells, we found that Gnetin C shows significant inhibitory effect on cell proliferation, more potent effects in colony formation and wound healing assays than resveratrol or pterostilbene. Importantly, Gnetin C specifically and strongly downregulates MTA1 and ETS2 expression in prostate cancer cells. Taken together, our findings implicate the potential of Gnetin C in MTA1/ETS2-mediated chemoprevention and therapy in prostate cancer.
Citation Format: Urvi Kolhatkar, Kshiti Dholakia, Gabriela Sikorska, Avinash Kumar, Luis A. Martinez, Anait S. Levenson. Gnetin C as a candidate for targeted chemopreventive and therapeutic measures in prostate cancer [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 253.
Abstract 2533: Regulation of proliferation and metastasis gene expression by DAX-1 (NR0B1) in human breast cancer cells
Authors: Tzagarakis-Foster Christina 
Published: August 2018

Abstract
The orphan nuclear receptor DAX-1 (Dosage Sensitive Sex Reversal, Adrenal Hypoplasia Congenita, critical region on the X chromosome, gene 1) is known to serve an important role early on in mammalian sex determination as well as in the regulation of expression of steroid hormones. While it is unclear whether DAX-1 functions independently, DAX-1 has been demonstrated to act as a repressor of many nuclear hormone receptors, including ER, AR, PR, LRH-1 and SF-1. DAX-1 plays a role in select adult tissues, including gonadal tissue. However, it has also been shown to play a role in several types of cancer, though its specific function is not well understood. For example, in some types of cancer DAX-1 expression is upregulated, while in other cancers it is highly downregulated or completely absent. In an effort to better understand DAX-1 function both in normal and disease states, we examined the actions of DAX-1 in MCF7 breast cancer cells, which do not express the DAX-1 gene. We probed three different PCR arrays (breast cancer genes, proliferation genes and metastatic genes) to determine which genes were influenced by DAX-1 expression. With the introduction of DAX-1 in ERα positive breast cancer cells (MCF-7), we find that DAX-1 inhibits cell proliferation and blocks estradiol activation of key cell cycle regulatory genes, such as cyclin D1, as well as important metastatic genes. We show that DAX-1 binds directly to ERα and the ERα-DAX-1 complex binds to the cyclin D1 promoter. The outcome of DAX-1 expression in MCF7 cells is cell cycle arrest through the repression of key cell cycle regulatory genes. These results demonstrate that DAX-1 functions as a corepressor of ERα in MCF7 breast cancer cells by preventing the activation of growth-promoting genes and decreasing cell proliferation in response to estrogens. These findings could have significant implications for future drug development strategies specifically aimed at ER-interacting proteins such as DAX-1.
Citation Format: Christina Tzagarakis-Foster. Regulation of proliferation and metastasis gene expression by DAX-1 (NR0B1) in human breast cancer cells [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 2533.
Abstract 254: Chemopreventive effects of angiotensin II receptor type 2 agonist on prostate carcinogenesis by the downregulation of the androgen receptor
Authors: Uemura Hiroji , Ito Yusuke , Naiki-Ito Aya , Kato Hiroyuki , Suzuki Shugo , Kuno Toshiya , Takahashi Satoru 
Published: August 2018

Abstract
[Background] We previously reported that angiotensin II receptor blockers (ARB), anti-hypertensive drug, have chemopreventive and chemotherapeutic potential against prostate cancer via the reduction of androgen receptor (AR) expression. It is generally known that angiotensin II binds to two kinds of receptors, AT1R and AT2R, and the biological function of AT2R signaling has the opposite effect to that of AT1R signaling in many aspects. We therefore hypothesized that AT2R agonism might attenuate the proliferative activity in prostate cancer cells. In this study, we investigated the effects of the AT2R agonist Compound 21 (C21) designed by Vicore Pharma (Sweden), which is expected to play similar roles to an ARB, on prostate carcinogenesis using the transgenic rat for adenocarcinoma of prostate (TRAP) model previously established in our laboratory.
[Materials and Methods] In vitro analyses of the cell growth, Western blotting and PSA-reporter gene assays were performed using LNCaP and 22RV1 cells. TRAP rats at 6 weeks of age were randomly divided into 3 groups of 12 animals each and treated with C21 at 1 or 2 mg/kg/day in drinking water for 12 weeks. They were pathologically examined the classification as prostatic intraepithelial neoplasia and non-invasive adenocarcinoma. The proteins extracted from TRAP prostate glands were examined for Western blotting.
[Results] C21 reduced the proliferation activity of prostate cancer cells and down-regulated the PSA promoter activity, medium PSA levels and the AR protein expression. We discovered that C21 inhibited the progression of prostate carcinogenesis in TRAP rats and decreased the incidence of adenocarcinoma in the lateral prostate. A significant increase in the apoptotic index with activation of caspase 3 and 7 were observed by immunohistochemistry and Western blotting analyses. C21 also down-regulated the expression of AR significantly in TRAP rat prostate. C21 decreased the expression of AR and AR-relevant genes reduced the proliferation activity effectively in prostate cancer cells and TRAP rat prostate.
[Conclusion] The present study demonstrated that the epoch-making AT2R agonist C21 down-regulated the proliferation activity and the expression of AR both in vitro and in vivo. C21 is a promising drug not only for hypertension but also for human prostate cancer chemoprevention.
Citation Format: Hiroji Uemura, Yusuke Ito, Aya Naiki-Ito, Hiroyuki Kato, Shugo Suzuki, Toshiya Kuno, Satoru Takahashi. Chemopreventive effects of angiotensin II receptor type 2 agonist on prostate carcinogenesis by the downregulation of the androgen receptor [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 254.
Abstract 2540: TRIM24 is an oncogenic transcriptional co-activator of STAT3 in glioblastoma
Authors: Lv Deguan , Li Yanxin , Zhang Weiwei , Alvarez Angel A. , Tang Jianming , Hu Bo , Cheng Shi-Yuan , Feng Haizhong 
Published: August 2018

Abstract
Aberrant amplification and mutations of epidermal growth factor receptor (EGFR) are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive pathogenesis are not well understood. Here, we determine that non-canonical histone signature acetylated H3 lysine 23 (H3K23ac)-binding protein tripartite motif-containing 24 (TRIM24) is upregulated in clinical GBM specimens and required for EGFR-driven tumorigenesis. In multiple glioma cell lines and patient-derived glioma stem cells (GSCs), EGFR signaling promotes H3K23 acetylation and association with TRIM24. Consequently, TRIM24 functions as a transcriptional co-activator and recruits STAT3, leading to stabilized STAT3-chromatin interactions and subsequent activation of STAT3 downstream signaling, thereby enhancing EGFR-driven tumorigenesis. Our findings uncover a pathway in which TRIM24 functions as a signal relay for oncogenic EGFR signaling and suggest TRIM24 as a potential therapeutic target for GBM that are associated with EGFR activation.
Citation Format: Deguan Lv, Yanxin Li, Weiwei Zhang, Angel A. Alvarez, Jianming Tang, Bo Hu, Shi-Yuan Cheng, Haizhong Feng. TRIM24 is an oncogenic transcriptional co-activator of STAT3 in glioblastoma [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 2540.