bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4719: Alterations of chromatin structure and TGF-β signaling in ARID1A-mutated colon cancer cells
Authors: Kim Jiwon , Jang Giyong , Lee Soo-Jin , Lee Sang Eun , Cho Sung-Yup 
Published: April 2023

Abstract
ARID1A, a subunit of the SWI/SNF complex which regulates gene expression by remodeling chromatin structure, is often mutated in various cancer and is known as a tumor suppressor gene. Many studies revealed the loss of ARID1A promotes tumor progression by activating PI3K-Akt signaling, but other pathways have not yet been fully elucidated. By analyzing RNA sequencing data and ATAC-seq data with ARID1A wild-type cell lines HCT116 and isogenic ARID1A Q456*/Q456* which has truncation mutations for ARID1A, we investigated the alterations of epigenomic and transcriptomic characteristics according to the loss of ARID1A. The overall openness of chromatin decreased in ARID1A Q456*/Q456* cells. Since SWI/SNF complex regulates chromatin structure and gene expression accordingly, we analyzed genes whose change of RNA expression and openness of chromatin in the same direction. The results showed 109 upregulated genes and 715 downregulated genes compared to wild type cell line with Padj &lt; 0.05, |log2FC| &gt; 0.58 from both RNA sequencing and ATAC-seq. To determine which gene sets are activated in the ARID1A-deficient cell line, the differentially expressed genes with consistent chromatin openness were subjected to Gene Ontology analysis. The upregulated genes in the ARID1A-deficient cell line were enriched in ‘Cell proliferation’ and ‘TGF-β signaling’. In addition, the expression of representative genes associated with TGF-β signaling increased in ARID1A-deficient cells. Our data suggests that loss-of-mutation in ARID1A significantly changes the chromatin structure, resulting in alterations of gene expression associated with cell proliferation and TGF-β signaling.
Citation Format: Jiwon Kim, Giyong Jang, Soo-Jin Lee, Sang Eun Lee, Sung-Yup Cho. Alterations of chromatin structure and TGF-β signaling in ARID1A-mutated colon cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4719.
Abstract 4721: Yin Yang 1-induced long non-coding RNA DUXAP9 drives oral squamous cell carcinoma by blocking CDK1-mediated EZH2 degradation
Authors: Cao Wei , Zhou Wenkai 
Published: April 2023

Abstract
Background: lncRNAs play a critical role in oral squamous cell carcinoma (OSCC) progression and metastasis. However, the detailed molecular mechanism is not fully understood.
Methods: Differential-expressed lncRNAs between OSCCs and paired adjacent tissues were identified by microarray. The expression of lncRNADUXAP9 (DUXAP9) was detected by RNAscope and quantitative real-time PCR (qRT-PCR). The gain-of-function and loss-of-function of DUXAP9 were evaluated in vitro and in vivo assays. Chromatin immunoprecipitation (ChIP)and luciferase assays were performed to analyze the transcriptional regulation of DUXAP9. RNA pull-down assays, LS-MS/MS analysis, RNA immunoprecipitation assays, and Co-immunoprecipitation (Co-IP) were performed to address the molecular mechanism through which DUXAP9promotes OSCC progression.
Results: By analyzing lncRNA microarray data, we identified a novel nuclear-localized DUXAP9, which is upregulated in OSCC. The high level of DUXAP9is positively associated with lymph-node metastasis, poor pathological differentiation, advanced clinical stage, worse overall survival, and worse disease-specific survival in OSCC patients. DUXAP9 significantly promotes cell proliferation, migration/invasion, and metastasis in vitro and in vivo through an EZH2-dependent manner. Yin Yang 1(YY1) was found to activate the transcriptional expression of DUXAP9 in OSCC. Furthermore, DUXAP9was proven to physically interact with EZH2 and inhibit EZH2 degradation via the suppression of the phosphorylation of EZH2, thereby blocking EZH2nucleus to cytoplasm translocation.
Conclusions: Here we demonstrated a novel mechanism mediated by lncRNA DUXAP9 at the posttranslational level, which contributes to OSCC progression, thus providing a promising target for OSCC therapy.
Keywords: LncRNA DUXAP9, YY1, EZH2, Ubiquitination, Oral squamous cell carcinoma
Citation Format: Wei Cao, Wenkai Zhou. Yin Yang 1-induced long non-coding RNA DUXAP9 drives oral squamous cell carcinoma by blocking CDK1-mediated EZH2 degradation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4721.
Abstract 4726: KMT5C-dependent regulation of mesenchymal-related genes and identification of KMT5C interactome using BioID
Authors: Son Jihye , Agredo Alejandra , Glaws Ally , Kasinski Andrea L. 
Published: April 2023

Abstract
Epigenetic dysregulation has recently been recognized as a new hallmark of cancer. Dysregulation of chromatin remodelers is estimated to affect 10-20% of cancer. Thus, understanding how epigenetic-based mechanisms contribute to cancer initiation and progression is critical. KMT5C is a histone methyltransferase that catalyzes histone H4 lysine 20 trimethylation (H4K20me3), which has historically been associated with formation and maintenance of constitutive heterochromatin regions. Albeit recent evidence from our lab also suggests regulation of gene-rich euchromatin regions. In this previous body of work we discovered that loss of KMT5C promotes development of resistance to tyrosine kinase inhibitors (TKI) in EGFR-mutant non-small cell lung cancer (NSCLC) cells (PC9 and HCC827). Patient data further supports that the KMT5C transcript level is downregulated following resistance to osimertinib, a third-generation TKI. Our data suggests that KMT5C is involved in non-canonical regulation of genes outside of heterochromatic regions through its methyltransferase activity. Analysis of data deposited into the Cell Miner database and publicly available RNA-sequencing and ChIP-sequencing data revealed that the KMT5C-H4K20me3 axis has significant negative correlations with several genes involved in epithelial-to-mesenchymal transition (EMT). Our validation studies support this observation. However the mechanisms involved in KMT5C facilitating this change at EMT-related genes is unknown. KMT5C is well understood to be recruited to heterochromatin regions through its interaction with HP1, yet the mechanism for recruitment of KMT5C to gene-rich euchromatin regions remains to be elucidated. We hypothesize that KMT5C is recruited to its target genes in euchromatin in an HP1-independent mechanism. In this study, we aim to identify the interactome of KMT5C using an unbiased proximity labeling BioID approach. This study is expected to uncover a novel epigenetic mechanism that contributes to development of resistance to TKIs and may inform of strategies to target KMT5C-downregulated TKI-resistant cancers.
Citation Format: Jihye Son, Alejandra Agredo, Ally Glaws, Andrea L. Kasinski. KMT5C-dependent regulation of mesenchymal-related genes and identification of KMT5C interactome using BioID. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4726.
Abstract 4796: Chemotherapy induced senescence drives peripheral neuropathy
Authors: Malachowski Taylor , Raut Ganesh , Bagchi Satarupa Mullick , Stewart Shelia 
Published: April 2023

Abstract
Chemotherapy is a mainstay of cancer therapy. Unfortunately, while chemotherapy can profoundly impact disease free survival, it’s often accompanied with devastating side effects, including peripheral neuropathy. Indeed, 30-40% of patients treated with neurotoxic chemotherapy develop long-term and often debilitating chemotherapy-induced peripheral neuropathy (CIPN). Unfortunately, there are currently no preventative measures for CIPN and while it is transitory in some patients, for others the side effects can persist for months or even years after the cessation of chemotherapy. Recent work suggests that cellular senescence, which is robustly induced by chemotherapy, contributes to CIPN. Senescent cells are typically characterized by increased CDKn2a (i.e., p16) expression, increased SA-β-gal hydrolyzation, and expression of the senescence-associated secretory phenotype (SASP) that can influence multiple cell types in the microenvironment. Through utilization of a mouse model that employs paclitaxel (PTX), we find that PTX robustly induces senescence in the hindpaws and dorsal root ganglia (DRG) of mice that display loss of peripheral axons and decreased response to mechanical stimuli. To address the role of senescence in CIPN, we utilized the INKATTAC mouse that allows for inducible elimination senescent cells. Using this model, we find that the elimination of senescent cells rescues CIPN. Further, the use of senolytics, drugs that kill senescent cells, also rescues CIPN, raising the possibility that we can treat patients with CIPN. To address the mechanism behind CIPN we have carried out single cell RNA-Seq to identify the population of senescent cells senescing in response to chemotherapy. These analyses will allow us to understand the mechanisms that drive CIPN and may lead to new treatments for patients suffering from CIPN.
Citation Format: Taylor Malachowski, Ganesh Raut, Satarupa Mullick Bagchi, Shelia Stewart. Chemotherapy induced senescence drives peripheral neuropathy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4796.
Abstract 4816: Targeting GCN2 regulation of amino acid homeostasis sensitizes prostate cancer cells to senolytic therapies
Authors: Sommers Noah R. , Cordova Ricardo A. , Klunk Angela J. , Pili Roberto , Wek Ronald C. , Staschke Kirk A. 
Published: April 2023

Abstract
The integrated stress response (ISR) features a family of eIF2 kinases that sense cellular stress, triggering translational and transcriptional modes of gene expression that enhance cell adaptation to the underlying stress. Previously we reported (Cordova et al., 2022 eLife) that prostate cancer (PCa) cells rely on one of these eIF2 kinases, GCN2, for maintenance of amino acid homeostasis and sustained proliferation. GCN2 functions to enhance expression of amino acid transporters and subsequent import of essential amino acids (EAAs) that are necessary to sustain PCa growth. Genetic loss or pharmacological inhibition of GCN2 results in decreased expression of amino acid transporters, severe depletion of intracellular EAAs, and decreased proliferation of PCa cells in culture and mouse xenograft models. Although loss of GCN2 in PCa cells reduces proliferation, depletion of this eIF2 kinase is suggested to lead to cell stasis and modest cell death. We hypothesize that the static phenotype by GCN2 inhibition in PCa cells renders these cells vulnerable to senolytic treatment and is a potential therapeutic target in combination therapies. To address this idea, we utilized models of androgen-sensitive and castration-resistant PCa and non-tumorigenic prostate epithelial cells. GCN2 inhibition induced a static phenotype in PCa cell lines, but not non-tumorigenic prostate epithelial cells, and this was accompanied by increased expression of the senescent markers p53, p21, p27, and MCL-1. Furthermore, induction of senescent markers following GCN2 inhibition in PCa cells was reversed by supplementation with EAAs, suggesting that limitation of EAAs is critical to the induction of cell stasis. Of importance, treatment of PCa cells with Navitoclax, a senolytic agent that targets Bcl-2 family of anti-apoptotic proteins, in combination with GCN2 inhibition resulted in enhanced cell death and apoptosis compared to each single treatment alone. Our results suggest that GCN2 inhibition in PCa cells leads to depletion of EAAs and induction of a static phenotype, rendering these cells vulnerable to targeting the Bcl-2 family of proteins to expedite cell death. As such, therapies integrating GCN2 inhibition and senolytic agents are proposed to be effective strategies for treatment of PCa.
Citation Format: Noah R. Sommers, Ricardo A. Cordova, Angela J. Klunk, Roberto Pili, Ronald C. Wek, Kirk A. Staschke. Targeting GCN2 regulation of amino acid homeostasis sensitizes prostate cancer cells to senolytic therapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4816.
Abstract 4819: Mechanism of disturbance of nuclear size homeostasis in cancer cells
Authors: Kim Changgon , Kim Joon 
Published: April 2023

Abstract
Abnormal increase in nuclear size is one of the criteria for distinguishing cancer cells. The main causes and functional consequences of nuclear size increase in cancer cells are not well known. In this study, we analyzed genome-wide RNAi library screen data to discover genes involved in the maintenance of nuclear size homeostasis. Importantly, many of the screen hits mapped to the functional categories of replication stress and DNA damage repair. We confirmed that depletion of genes required to prevent replication fork collapse causes a significant increase in nuclear size. Excessive replication stress and defects in the DNA repair system are common in many cancers. Therefore, disturbances of nuclear size homeostasis may be due to excessive replication stress and enhanced DNA damage response. To identify effectors that link replication stress and nuclear size change, we investigated candidates such as cell cycle progression, the mTOR pathway, and the cytoskeleton. As previously known, cell cycle arrest at G2 phase increased nuclear size, but replication fork collapse increased nuclear size even more excessively, suggesting the existence of other mechanisms. Inhibition of the mTOR pathway did not block replication stress-induced nuclear enlargement. Interestingly, we found that actin polymerization inside the nucleus plays a role in determining nuclear size in replication stress condition. Inhibition of nuclear actin polymerization reversed nuclear enlargement due to replication fork collapses. The Increase in nuclear size appeared to reduce the invasive ability of cancer cells. In addition, the enlarged nuclei resisted mechanical stress-mediated nuclear envelope rupture. We also observed a change in the abundance of the tri-methylation of lysine 27 on histone H3. These results suggest that nuclear size homeostasis is perturbed as a result of excessive replication stress, and changes in nuclear size affect the invasive capacity and gene expression of cancer cells. However, it is not clear whether nuclear enlargement act as a strong barrier to metastasis, as nuclear size can readily change through changes in nuclear actin dynamics. Further studies are needed to understand the impact of nuclear size changes on cancer initiation and progression.
Citation Format: Changgon Kim, Joon Kim. Mechanism of disturbance of nuclear size homeostasis in cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4819.
Abstract 4821: Exploring the role of a solid-like condensate in breast and prostate cancer
Authors: Grunfeld Alexander , Bokros Michael , Kirk Chloe , Lee Stephen 
Published: April 2023

Abstract
Cancer cells are exposed to harsh environmental conditions, which they adapt to by engaging various stress response pathways. A common cellular response to these stressors is the assembly of membraneless compartments known as biomolecular condensates. Our lab discovered one such pathway where exposure to environmental stressors reversibly converts nucleoli into solid-like condensates known as Amyloid bodies (A-bodies). A-bodies induce a state of cellular dormancy by sequestering in an amyloid-like state key proteins involved in processes such as DNA replication and cell cycle progression. In vitro experiments showed that suppressing A-body formation in cancer cell lines accelerates tumorigenesis, suggesting that system-wide amyloidogenesis is a mechanism of tumor suppression. The goal of this project was to investigate how A-bodies correlate with tumorigenesis in the context of human tissues. Using formalin-fixed paraffin embedded (FFPE) sections of breast invasive ductal carcinoma and prostate adenocarcinoma, we first confirmed the presence of A-bodies in tumors by staining with the amyloidophilic dye Amylo-glo. In agreement with in vitro data in breast and prostate cancer cell lines, immunohistochemical staining further showed these condensates contain known A-body constituent proteins. Co-staining tissues with Amylo-glo and the proliferation marker Ki67 revealed a negative correlation between A-bodies and cell proliferation, supporting the hypothesis that A-bodies suppress cell growth. Finally, tissue staining comparing primary tumors with distant metastases suggests that A-body biogenesis is reduced in the progression to metastatic disease. Together, our preliminary data presents a biomolecular condensate which can be visualized in human tissues and inversely correlates with cell proliferation. Future directions include examining additional tumor types for the presence of A-bodies and testing the correlation between A-bodies and other markers of proliferation, cell cycle arrest, and environmental stress.
Citation Format: Alexander Grunfeld, Michael Bokros, Chloe Kirk, Stephen Lee. Exploring the role of a solid-like condensate in breast and prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4821.
Abstract 4932: The role of KB-S in treating pancreatic cancer
Authors: Boshra Sadia Noosrat , Bisht Kirpal , Acevedo-Duncan Mildred 
Published: April 2023

Abstract
Pancreatic cancer remains one of the most lethal malignant cancers because the symptoms of this cancer do not exhibit until the disease progresses to an advanced stage. Late diagnosis may result in metastasis. When metastasis occurs, cancer can no longer be removed with surgery and therefore, requires treatment with FDA approved chemotherapeutic drugs or radiotherapy and they often fail to treat the disease. KB-S is a synthetic thymidine nucleoside analogue which is broadly used for the treatment of Human Immunodeficiency Virus (HIV). In this work, we explored the therapeutic potential of KB-S as an anticancer drug, with focused against pancreatic cancer. Our aim is to establish a connection between cellular kinase of KB-S and atypical protein kinase C (aPKC) to decipher signaling pathways. Pancreatic adenocarcinoma, ASPC-1 cell line was used for the study. Hemocytometer was used for cell counting for the dose response curve after treating with KB-S. Immunoprecipitation study was conducted using anti-PKC-iota beads. Western blot assay was performed using primary antibody PKC-zeta and a secondary antibody. Our results showed that KB-S decreases cell proliferation significantly on AsPC-1 cells over increasing the concentrations. KB-S decreased the proliferation by 20% for 0.5 µM (P≤ 0.09), 37% for 5 µM (P≤ 0.02), 44% for 10 µM (P≤ 0.01), 48% for 20 µM (P≤ 0.002) and 54% for 50 µM (P≤ 0.001) in AsPC-1 cells. We used the lowest concentration of 10 µM with significant inhibition for further experiments. We immunoprecipitated for PKC-ι and immunoblotted for PKC-ζ and the immunoblots showed that there is no association between PKC-ι and PKC-ζ in pancreatic cancer cell line (AsPC-1). But when we performed reverse immunoprecipitation, we found that there is an association between PKC-ι and PKC-ζ. Again, we immunoprecipitated for thymidine kinase and immunoblotted for PKC-ι and immunoblots showed that there is an association between thymidine kinase and PKC-ι. But when we did the reverse immunoprecipitation, we did not find any association between thymidine kinase and PKC-ι in pancreatic cancer cell line. Based on our preliminary studies, we report the anti-cancer effect of KB-S in treating a pancreatic cancer cell line leading to further future investigations. To the best of our knowledge, this is the first demonstration of therapeutic efficacy of KB-S against a cancer. Given that, KB-S is already approved by FDA for the treatment of HIV, it carries the potential to be repurposed for difficult to cure cancerous diseases such as pancreatic cancer.
Citation Format: Sadia Noosrat Boshra, Kirpal Bisht, Mildred Acevedo-Duncan. The role of KB-S in treating pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4932.
Abstract 4962: Discovery of cancer-specific E3 ligase ligands for targeted protein degradation
Authors: Wang Zhaofu , Zhang Lynette , Chang Zhen , Zhao Mengxi , Li Guobin , Qin Fang , Ma Shichao , Li Yunfeng , Zhang Zhongguo , Wang Xinghao , Kong Ying , Lou Shidi , Chen Sheng , Liu Lanzhen , Xu Shuaijie , Zhang Hailong 
Published: April 2023

Abstract
F-box/WD repeat-containing protein 7 (FBXW7) is the substrate recognition component of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. FBXW7 recognizes and binds phosphor-degrons within target proteins and capture them to SCF complex for ubiquitination. Know FBXW7 substrates include cyclin-E, DISC1, JUN, MYC, NFE2L1, NOTCH2, MCL1, RICTOR, and NOTCH1 released notch intracellular domain (NICD). FBXW7 is frequently mutated in cancer, results in loss of substrate recognition and binding. R465C is a one of the major FBXW7 mutations and is found in over 70,000 cancer patients worldwide. From a high-throughput screen, we discovered compounds that selectively bind to FBXW7 R465C mutant. PROTACs against various protein targets have been made with these mutant specific ligands. Some of these PROTACs could induce targeted protein degradation in cells carrying FBXW7 R465C mutant but not wild-type FBXW7. Targeted protein degradation with these PROTACs could represent a novel therapeutic approach against FBXW7 R465C mutant cancer.
Citation Format: Zhaofu Wang, Lynette Zhang, Zhen Chang, Mengxi Zhao, Guobin Li, Fang Qin, Shichao Ma, Yunfeng Li, Zhongguo Zhang, Xinghao Wang, Ying Kong, Shidi Lou, Sheng Chen, Lanzhen Liu, Shuaijie Xu, Hailong Zhang. Discovery of cancer-specific E3 ligase ligands for targeted protein degradation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4962.