bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1420: The non-canonical role of Rb in enhancers and insulators
Authors: Lee Hanjun , Gkotinakou Ioanna M. , Sanidas Ioannis , Lawrence Michael S. , Dyson Nicholas J. 
Published: April 2023

Abstract
Despite the great significance of the tumor suppressor Rb in cancer biology, the full spectrum of its binding pattern in human cells was yet to be established. Here, we report that rather than exclusively associating with E2F-bound promoters, chromatin-bound Rb associates with three distinct types of loci—E2F1-bound promoters, AP-1-bound enhancers, and CTCF-bound insulators. The binding pattern of Rb correlated with cohesin binding and chromatin accessibility in all three types of Rb-bound regions. When cells entered the S phase after the G1/S checkpoint, Rb redistributed from promoters to enhancers, leading to distinct transcriptional changes. These Rb-bound enhancers were cell-type-specific, in contrast to Rb-bound promoters that were constitutively present throughout most human cell types. Overall, our study provides a comprehensive view on the role of the tumor suppressor Rb, which has a well-preserved role in the G1 phase of regulating transcription at E2F1-bound promoters, while having a cell-type-specific role in the S phase when cells are determined to replicate.
Citation Format: Hanjun Lee, Ioanna M. Gkotinakou, Ioannis Sanidas, Michael S. Lawrence, Nicholas J. Dyson. The non-canonical role of Rb in enhancers and insulators [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 1420.
Abstract 1423: Regulation of SKP2 expression by methyltransferase-independent function of EZH2 in tumor growth and progression
Authors: Colon Tania Marlyn , Dai Wei , Choi Byeong Hyeok 
Published: April 2023

Abstract
Skp2, an F box protein and a substrate-binding component of the SCFSkp2 ubiquitin E3 ligase complex, promotes ubiquitination and degradation of cyclin-dependent kinase inhibitors (CKIs), including p21, p27, and p57. Aberrant Skp2 expression is associated with many human cancers. EZH2 (Enhancer of Zeste Homologue 2) is a core catalytic subunit of the polycomb repressive complex 2 (PRC2) that can regulate gene expression by mediating the methylation of lysine 27 of histone H3 (H3K27me3). Accumulating evidence shows that EZH2 could bind to transcription factors and activate gene expression independently of its methyltransferase activity, leading to the activation of oncogenic signaling pathways and promoting the proliferation of tumor cells. Although the methyltransferase-independent function of EZH2 is important in cell proliferation, its mechanism in cell cycle regulation is still unclear. In this study, we demonstrate that EZH2 positively regulates Skp2 gene expression. We show that suppression of EZH2 expression resulted in a significant decrease of Skp2 protein levels, while the EZH2 enzymatic inhibitors, EPZ6438, had no impact on protein levels of Skp2, which suggests that EZH2 regulates Skp2 expression independently of its methyltransferase activity. Consistently, EZH2 depletion reduced the mRNA levels of Skp2, while EPZ6438 inhibited EZH2 methyltransferase activity without affecting the mRNA levels of Skp2. Importantly, EZH2 expression is positively correlated with the expression of EMT (Epithelial-mesenchymal transition) regulators (YAP1/TAZ, ZEB1, and Snail) and immune checkpoint proteins (FGL1 and Siglec-15) in cervical and pancreatic cancer cells, but reversely correlated with the expression of CKIs (p21, p27, and p57). Taken together, our findings suggest a novel mechanism by which EZH2 regulates tumorigenesis through its methyltransferase-independent function by regulating Skp2 expression. Targeting the methyltransferase-independent function of EZH2 may have therapeutic efficacy for cancer patients.
Citation Format: Tania Marlyn Colon, Wei Dai, Byeong Hyeok Choi. Regulation of SKP2 expression by methyltransferase-independent function of EZH2 in tumor growth and progression [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 1423.
Abstract 1448: The YAP1/TEAD and NF-Kappa B transcription factors may cooperate to mediate prostate cancer progression
Authors: Cinar Bekir , Al-Mathkour Marwah M. , Dwead Abdulrahman M. , Boston Ava M. , Lewis Michael S. , Moreno Carlos S. 
Published: April 2023

Abstract
Metastatic castration-resistant prostate cancer is morbid and lethal. The transcriptional coregulator YAP1 (Yes-associated protein 1) is a nuclear effector of the Hippo pathway. The Hippo pathway regulates cell growth, motility, and carcinogenesis. Here, we investigated biochemical and functional interactions between YAP1 and the nuclear factor (NF) kappa B/RELA subunit in prostate cancer cell models. We demonstrated that endogenous YAP1 and RELA form protein complexes in the cell, as revealed by co-immunoprecipitation and western blotting. Compared with control, we found that combined treatment of cells with androgen and SDF1a (stromal cell-derived factor-1 alpha) or RANKL (receptor activator of NF-kappa Β ligand) enhanced the protein-protein interaction between YAP1 and RELA, as showed by proximity ligation assay. Our confocal microscopy experiment further showed that combined SDF1a and androgen treatment augmented the YAP1 and RELA colocalization relative to single-agent. Moreover, our promoter-reporter and RNAi experiments showed that genetic silencing YAP1 or TEAD protein, a key mediator of the YAP1 transcription, significantly reduced the NF-Kappa B promoter-reporter gene activity. Also, disruption of YAP1 activity by genetic and small molecule attenuated endogenous protein-protein interaction between TEAD and RELA. Furthermore, controlled expression of MST1/STK4, a potent inhibitor of YAP1, suppressed the NF-Kappa B-promoter reporter activity. Additionally, our unbiased bioinformatics analysis of the exiting ChIP-seq (chromatin immunoprecipitation-sequencing) data identified several genes likely co-regulated by the TEAD1-4 and NF-Kappa B transcription factors. Besides, our computational analysis of the TCGA and Stand Up To Cancer (SU2C) prostate cancer data sets indicated that expression of YAP/TEAD and NF-kappa B/RELA correlates in clinical cases. These findings suggest that cooperative androgen and cytokine signaling regulates Hippo/YAP and NF-Kappa B interaction and their functions. These may have critical roles in advanced prostate cancer downstream of the Hippo pathway.
Citation Format: Bekir Cinar, Marwah M. Al-Mathkour, Abdulrahman M. Dwead, Ava M. Boston, Michael S. Lewis, Carlos S. Moreno. The YAP1/TEAD and NF-Kappa B transcription factors may cooperate to mediate prostate cancer progression [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 1448.
Abstract 1460: Co-expression network analysis reveals male breast cancer specific transcriptional module
Authors: Gou Xuxu , Wang Junkai , Lei Jonathan T. , Jaehnig Eric J. , Anurag Meenakshi 
Published: April 2023

Abstract
Introduction: According to the American Cancer Society, An estimated 2,710 men are diagnosed with breast cancer annually of which about 530 die due to the disease annually in the United States. Most male breast tumors are estrogen receptor positive. Risk factors include age, radiation exposure, BRCA1/2 gene mutations, Klinefelter syndrome, testicular disorders, diabetes, gynecomastia (enlarged breast) etc. Due to low testing and incidence rate and lack of bioinformatics approaches focused on identification of drivers of rare cancer, little is known about this disease in men than in women. Because of this knowledge-gap there is no therapy that is specifically tailored for male breast cancer, leading to nineteen percent higher mortality in male than female with breast cancer.
Method: In the past, gene expression analysis has revealed differential pathways in male than in female breast cancer, but these studies compared male and female tumors without considering innate (sex-specific) differences in the mammary tissues between the two sexes. To overcome these challenges, we have utilized publicly available tumor (E-TABM-810, TCGA-Breast) and normal (GTEX - mammary) datasets to identify pathways and gene co-expression networks enriched in specific transcription factor (TF) targets that are specific to male breast tumors . Findings from this analysis is further validated in male breast tumor patient derived xenograft (PDX) model.
Result: Using differential pathway analysis corrected by sex, Type I diabetes mellitus is the only Hallmark pathway signature that is significantly downregulated in male tumors compared to both female tumors and normal mammary tissue. No pathway is distinctively up-regulated in male tumors. Co-expression network analysis of gene expression datasets identified unique TF-driven networks that are specific to male breast tumors. This analysis identified a network of ELK1 and DMRT1 TF targets that are unregulated and downregulated in male breast tumors respectively. This was further validated in PDX dataset.
Conclusion: Based on our results, we hypothesize that loss of DMRT1 TF activity is potentially associated with occurrence of male breast tumors. The role of DMRT1 in sex differentiation and gonadal differentiation has been explored, but its role in male breast tumor formation is not as well characterized. Thus, our analysis provides novel insight in transcription factors associated with incidence of this rare form of cancer in men.
Citation Format: Xuxu Gou, Junkai Wang, Jonathan T. Lei, Eric J. Jaehnig, Meenakshi Anurag. Co-expression network analysis reveals male breast cancer specific transcriptional module [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 1460.
Abstract 1490: Exon exclusion of NELF-E produces an anti-tumorigenic truncated isoform in hepatocellular carcinoma
Authors: Reynolds Laura , Lamm Ryan , Barry Anna , Grim Meghan , Zhang Kai , Dang Hien 
Published: April 2023

Abstract
Overexpression of negative elongation factor E (NELF-E), a subunit of the negative elongation factor (NELF) complex involved in transcription pausing, has been implicated in poor hepatocellular carcinoma (HCC) outcome. We recently discovered an intronic heterozygous single nucleotide polymorphism (SNP), rs79208225 (G&gt;A), near a spliceosome binding site in less than 1% of the general population but ~4% of our HCC cohort. HCC patients with the SNP had significantly longer times till recurrence (p=0.001) and better overall survival (p=0.02) compared to patients without the SNP. Using the minigene assay, we found the SNP causes exon 10 exclusion, which resulted in lower levels of full length NELF-E and the presence of a truncated NELF-E isoform that was not degraded via RNAi surveillance. We hypothesize NELF-E isoform switching is anti-tumorigenic in HCC. To investigate the effects of exon 10 exclusion, we employed antisense oligonucleotides (ASOs). HCC cells treated with ASOs had decreased cell proliferation and colony formation. Moreover, exon 10 exclusion enriched for the truncated NELF-E isoform and decreased full length mRNA and protein expression. Genetic models (CRISPR/cas9) showed similar phenotypes, suggesting that the truncated NELF-E is anti-tumorigenic. Currently, we are investigating the functional role of the truncated NELF-E protein in transcription regulation and the effects of isoform switching in HCC cells as a potential therapeutic strategy for HCCs with elevated NELF-E levels.
Citation Format: Laura Reynolds, Ryan Lamm, Anna Barry, Meghan Grim, Kai Zhang, Hien Dang. Exon exclusion of NELF-E produces an anti-tumorigenic truncated isoform in hepatocellular carcinoma [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 1490.
Abstract 1492: Interaction between Argonaute-2 and Negative Elongation Factor-E in hepatocellular carcinoma
Authors: Ruiz Brittany Natalie , Lucci Alvaro , Barry Anna , Zhang Kai , Dang Hien 
Published: April 2023

Abstract
Hepatocellular carcinoma (HCC) continues to be one of the leading cause of cancer-related deaths globally, whose incidence is on the rise in the United States. We and others have shown that high levels of AGO2 is associated with a worse prognosis in HCC patients. Specifically, we showed AGO2 promotes HCC progression by modulating MYC mRNA stability in an RNAi-independent manner. In addition to its canonical role as an RNA binding protein, AGO2 has been demonstrated to regulate gene expression by affecting RNA polymerase II (Pol II) pausing through the Negative Elongation Factor (NELF) complex in Drosophila. It remains elusive how AGO2 modulates the chromatin to affect transcription. Here, we hypothesize AGO2/NELF interactions modulate chromatin accessibility to promote HCC. Immunoprecipitation assays were employed to detect protein-protein interactions between AGO2 and the NELF complex in HCC cells. To determine the effects of AGO2 RNAi-silencing on their interaction, DICER-knockout (via CRISPR) HCC cell lines were also probed for protein-protein interactions. We found AGO2 and NELFE, a member of the NELF complex, interact in both wild-type and DICER-knockout HCC cell lines. These data suggest AGO2 may play an important role in modulating transcription through NELF. Currently, we are investigating the potential interplay between AGO2 and NELFE in modulating chromatin accessibility to promote hepatocarcinogenesis. Understanding the effects of the AGO2/NELF interaction may help elucidate transcriptional regulation in HCC and lead to better therapies for HCC patients.
Citation Format: Brittany Natalie Ruiz, Alvaro Lucci, Anna Barry, Kai Zhang, Hien Dang. Interaction between Argonaute-2 and Negative Elongation Factor-E in hepatocellular carcinoma [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 1492.
Abstract 1493: ROS inhibits enzymatic activation of PRMT5 and increases the protein stability of tumor suppressors as non-histone substrates in liver cancer
Authors: Lee Ji Min , Kim Hyunkyung , Im Hyuntae , Baek Hee-ji 
Published: April 2023

Abstract
Retinoic acid receptor-related orphan receptor α (RORα) and p53 are transcription factors involved in nuclear gene expression and known tumor suppressors. RORα was the first identified substrate of lysine methylation-dependent degradation. However, the mechanisms of other post-translational modifications (PTMs) that occur in RORα and p53 remain largely unknown, especially in liver cancer. Arginine methylation is a common PTM in arginine residues of nonhistone and histone proteins and affects substrate protein function and fate. We found an analogous amino acid disposition containing R37 at the ROR N-terminus compared to histone H3 residue, which is arginine methylated. Here, we provide evidence that R37 methylation-dependent degradation is carried out by protein arginine methyltransferase 5 (PRMT5). In addition, we discovered that PRMT5 regulated the interaction between the E3 ubiquitin ligase ITCH and RORα through RORα arginine methylation. Arginine methylation-dependent ubiquitination-mediated RORα degradation reduced downstream target gene activation. H2O2-induced reactive oxygen species (ROS) decreased PRMT5 protein levels, consequently increasing RORα protein levels in liver cancer in vitro and in vivo. Furthermore, the enzymatic activities of PRMT5 were directly affected by ROS via the dissociation of PRMT5-Mep50 octamer in the methylosome complex. Taken together, ROS inhibited liver cancer progression by inducing apoptosis via PRMT5-mediated methylation of RORα combined with other histone and non-histone substrates and the ITCH axis. Our results potentiate PRMT5 as an elimination target in cancer therapy, and this additional regulatory level within ROS signaling may help identify new targets for therapeutic intervention in liver cancer.
Citation Format: Ji Min Lee, Hyunkyung Kim, Hyuntae Im, Hee-ji Baek. ROS inhibits enzymatic activation of PRMT5 and increases the protein stability of tumor suppressors as non-histone substrates in liver 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 1493.
Abstract 157: Patient in the lab: Down-scaling patient-derived organoid screening for diagnostic purposes
Authors: Koedoot Esmee , van Weersch Inez , Harada Gakuro , Watanabe Masahiko , Warda Hamdy , Kyan Hideaki , Abouleila Yasmine , Kumagai Takahiko , Hikichi Yuichi , Overmeer René , Roodhart Jeanine , Matsuno Kiyotaka , Verissimo Carla , Boj Sylvia F. 
Published: April 2023

Abstract
Colorectal cancer (CRC) is the third leading cause of cancer and cancer-related death. A large fraction of the CRC patients diagnosed with de novo metastatic disease do not benefit from standard of care and experience substantial side effects. Therefore, there is an urgent need for preclinical models that help predict patient response in the clinic. Patient-derived organoids (PDOs or HUB Organoids®) represent a significant breakthrough as preclinical models as they are directly established from patient tissue and faithfully recapitulate patient disease. HUB Organoid Technology can already be applied to preclinical drug screening, however, to provide direct patient benefit the turnaround time between patient diagnosis and PDO-based results must be shortened. In collaboration with Yamaha Motor, the Yamaha CELL HANDLERTM has been validated to automatically pick-and-place with high accuracy a significantly reduced number of organoids per screening plate, compared to standard procedures. In addition, an image-based readout was developed that enables a precise quantification of organoid number ensuring high assay quality. Organoid responses to chemotherapy and targeted agents were validated using this newly automated system, confirming comparable PDO-patient drug sensitivity profiles, and known drug responses based on genetic dependencies. In summary we describe the development of an automated workflow that combines patient-representative HUB Organoids and state-of-the-art robotics by Yamaha CELL HANDLER. This workflow down-scales the number of organoids needed per screening well and allows to efficiently predict patient response, thereby reducing the diagnostic turnaround time and increasing patient benefits.
Citation Format: Esmee Koedoot, Inez van Weersch, Gakuro Harada, Masahiko Watanabe, Hamdy Warda, Hideaki Kyan, Yasmine Abouleila, Takahiko Kumagai, Yuichi Hikichi, René Overmeer, Jeanine Roodhart, Kiyotaka Matsuno, Carla Verissimo, Sylvia F. Boj. Patient in the lab: Down-scaling patient-derived organoid screening for diagnostic purposes [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 157.
Abstract 1571: The feasibility and pharmacological mechanism of cucurbitacin E for the treatment of EGFR-TKI-primary resistant NSCLC
Authors: Chen Chun-Han 
Published: April 2023

Abstract
Lung cancer ranks the leading cause of cancer death, with an estimated 1.8 million deaths according to the latest global cancer statistics. In the United States, there will be an estimated 236,740 new cases diagnosed, and 130,180 people will die from lung cancer in 2022. In non-small-cell lung cancer (NSCLC) patients, targeted therapies are available for patients with EGFR exon 19 deletion and L858R mutations. However, tumors harboring wild-type EGFR or Kras mutation are not eligible for targeted therapies. Therefore, the development of new drugs to treat primary resistant NSCLC remains urgent needs. Cucurbitacin E (CuE) is a tetracyclic triterpenoid compound extracted from the family of Cucurbitaceae. The data showed that CuE exhibits a significant antiproliferative effect with a GI50 value of 0.03±0.01 μM. Cell cycle analysis revealed that CuE induces G2/M arrest and down-regulates cell cycle regulatory proteins in A549 cells. CuE treatment further increased the expression of cleaved caspase-3/8/9/PARP, and altered the expression of DNA-damaged-related biomarkers. Meanwhile, protein levels of LC3BII and p62, and ROS production were upregulated by CuE. Pharmacological Inhibition of ATM reversed the effects of CuE on autophagy-related proteins. In summary, CuE is a potential drug for the treatment of primary resistant NSCLC.
Citation Format: Chun-Han Chen. The feasibility and pharmacological mechanism of cucurbitacin E for the treatment of EGFR-TKI-primary resistant NSCLC [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 1571.
Abstract 1573: Inhibition of acetyl-CoA carboxylase induced spindle abnormalities
Authors: Fang Chieh-Ting , Kuo Hsiao-Hui , Liu Sih-Long , Yao Jhong-Syuan , Yih Ling-Huei 
Published: April 2023

Abstract
Acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in the de novo fatty acid synthesis pathway, is required for successful cell division in yeast, indicating that fatty acid synthesis may be regulated in order to properly safeguard nuclear and cell division. ACC is also phosphorylated during mitosis and this inhibitory phospho-ACC is accumulated at the spindle pole at metaphases. In this study, we set out to understand the role of ACC in the regulation of mitotic spindle assembly in human cells. We found that inhibition of ACC with TOFA induced spindle defects and cell death. The spindle defects induced by TOFA could be rescued by exogenous palmitic acid (PA), the immediate products of fatty acid synthesis. Inhibiting protein palmitoylating or depalmitoylating enzymes could induced spindle defects. These data indicate that well-regulated cellular PA levels and protein palmitoylation are required to assure accurate spindle assembly. In addition, the spindle microtubules comprised of α-tubulins mutated at the reported palmitoylation site exhibited disrupted dynamic instability. These results reveal that ACC may modulate tubulin palmitoylation during mitosis to delicately control MT dynamic instability and spindle assembly, thereby safeguarding nuclear and cell division.
Citation Format: Chieh-Ting Fang, Hsiao-Hui Kuo, Sih-Long Liu, Jhong-Syuan Yao, Ling-Huei Yih. Inhibition of acetyl-CoA carboxylase induced spindle abnormalities [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 1573.