bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4521: Substrate profiling for SETD8 reveals novel protein targets involved in DNA replication and DNA damage response
Authors: Pittella Silva Fabio , Blum Gil , Senevirathne Chamara , Luo Minkui 
Published: July 2016

Abstract
Protein lysine methyltransferases utilize S-adenosyl-L-methionine (SAM) to catalyze the addition of methyl groups to specific lysine residues in both histones and non-histone proteins. Recent evidence indicates that their dysregulation is closely linked to the development and progression of cancer, making them potential therapeutic targets. SETD8 is the sole methyltransferase responsible for mono-methylation of histone H4 lysine 20 (H4K20me1). Its activity is essential for cell viability and has been associated with many essential cellular processes including transcriptional regulation, heterochromatin formation, genomic stability and cell-cycle progression. SETD8 is overexpressed in several types of cancer and may play important roles on malignancy through its trans-methylation activity or by direct interaction with its binding partners. It has been reported that the association between SETD8 and TWIST, a regulator of epithelial-mesenchymal transition, enhances the invasiveness of breast cancer cells. In addition, it was shown that SETD8-mediated methylation of p53 suppresses p53 dependent transcription activation in cancer cells. Despite the identification of a few non-histone proteins such as p53, PCNA and Numb as SETD8's substrates, a comprehensive investigation of new potential substrates is lacking to date. Here we used Bioorthogonal Profiling of Protein Methylation (BPPM) with engineered SETD8 and synthetic SAM analogues to profile novel substrates for SETD8. We identified SETD8 mutants amenable to accommodate non-native SAM analogues containing a terminal alkyne moiety for click chemistry. The engineered SETD8 can transfer this distinct chemical moiety into target proteins for subsequent pulldown and identification of the modified substrates. The BBPM technology applied here revealed previously known substrates of SETD8 as well as novel SETD8 targets. Among the main targets of our interest are those involved in DNA replication and DNA damage response. Our finding is expected to bring new perspectives on the biological importance of SETD8 as well as on its role in carcinogenesis.
Citation Format: Fabio Pittella Silva, Gil Blum, Chamara Senevirathne, Minkui Luo. Substrate profiling for SETD8 reveals novel protein targets involved in DNA replication and DNA damage response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4521.
Abstract 4522: Epstein-Barr virus infection suppresses the DNA repair mechanisms in nasopharyngeal epithelial cells via reduction of the H3K4me3 mark
Authors: Lung Maria L. , Cheung Arthur KL , Dai Wei , Leong Merrin ML , Tsao. George SW 
Published: July 2016

Abstract
Introduction: Epstein-Barr Virus (EBV) is an oncovirus, which contributes to development of various cancers, including nasopharyngeal carcinoma (NPC). EBV latent proteins play critical roles in modulation host cell histone modifications in order to regulate its signaling pathways. However, the role of EBV in regulation histone modifications in epithelia cell system is still not very clear. Further studies are necessary to characterize the functional role of EBV in regulating epithelial cell modifications.
Aim: in this current study, we aim to investigate the role of EBV infection in regulating a promoter and transcription activation histone marker, H3K4me3, in the host cell genome.
Methodologies: Chromatin immunoprecipitation sequencing (ChIPseq) was performed by using the next-generation sequencing approach. The ChIP reactions were prepared by utilizing the antibody targeting the H3K4me3 mark in two pairs of immortalized non-tumorigenic nasopharyngeal epithelial (NPE) cell lines, which were artificially infected with (550, 550-EBV, 361, and 361-EBV). The ChIPseq results were validated by the ChIP-QPCR and RT-QPCR.
Results: A total of 1747 genes show losses of H3K4me3 in both sets of EBV-infected NPE cell lines. Among them, 628 (36%) genes show losses of H3K4me3 in promoter regions. Interestingly, a total of 18 DNA damage repair signaling members in the base excision repair (BER), homologous recombination, non-homologous end-joining, and the mismatch repair pathways showed significant losses of H3K4me3 in EBV-infected NPE cells. Based on utilizing the DAVID annotation tool for pathway analysis, members in the BER pathway were significantly enriched (FDR = 0.0709, cut-off&lt;0.1). The ChIPseq results were validated by ChIP- and RT-QPCR and showed significant losses of the H3K4me3 and expression of the BER members in both sets of EBV-infected NPE cell lines. The clinical significances were further confirmed by detection of significant down-regulation of the BER members in NPC paired biopsies.
Conclusion: EBV infection induces changes of host cell H3K4me3 levels and results in down-regulation of the BER members.
Acknowledgement: This work was supported by the Research Grants Council of the Hong Kong Special Administrative Region, People's Republic of China: Grant number AoE/M-06/08 to MLL and the Seed Funding Programme for Basic Research of the University of Hong Kong: Grant number 201308159003 to AKLC.
Citation Format: Maria L. Lung, Arthur KL Cheung, Wei Dai, Merrin ML Leong, George SW Tsao. Epstein-Barr virus infection suppresses the DNA repair mechanisms in nasopharyngeal epithelial cells via reduction of the H3K4me3 mark. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4522.
Abstract 4523: Decreased H2B monoubiquitination is associated with enhanced proliferation and resistance to apoptosis in human lung cancer
Authors: Zhang Keqiang , Wang Jinhui , Wu Xiwei , Reno Theresa A. , Tong Tommy R. , Kim Jae , Raz Dan 
Published: July 2016

Abstract
Monoubiquitination of histone H2B (H2Bub1) is an important chromatin modification that plays multiple roles in transcription, mRNA processing, DNA repair, cell differentiation, and maintenance of stemness. Recent studies have indicated that dysregulation of H2Bub1 and the resulting alterations of global gene expression are key contributors in cellular transformation and metastasis. However, the importance of H2B ubiquitination in lung cancer is unknown. Here, by using immunohistochemical analysis (IHC), we have demonstrated that the protein level of H2Bub1 is frequently decreased in a cohort of human lung cancer tissues in comparison to paired adjacent normal tissues. We also found that decrease in H2Bub1 is associated with increased cellular proliferation, as measured by Ki67, and is associated with decreased overall survival. Furthermore, using RNA-seq and transcriptional profiling analysis, we identified that reduction of H2Bub1 via attenuating the expression of histone H2B E3 ubiquitin ligase ring finger protein 20 (RNF20) leads to significant changes of global gene expression, modulating multiple malignancy-promoting genes, including c-Met, E2F2, and BMF. Signaling pathways including p53, DNA replication, DNA repair, and cellular proliferation, and regulation of apoptosis in lung cancer cells are also altered. Additionally, we have further shown that decrease of H2Bub1 by RNF20 knockdown significantly promotes growth, migration/invasion, and strongly enhances resistance to cytotoxic chemotherapy-induced apoptosis in lung cancer cells. Our findings suggest that dysregulation of H2Bub1 signaling may play an important role in growth and drug resistance of lung cancers, and may potentially serve as a prognostic biomarker and therapeutic target for lung cancer patients.
Citation Format: Keqiang Zhang, Jinhui Wang, Xiwei Wu, Theresa A. Reno, Tommy R. Tong, Jae Kim, Dan Raz. Decreased H2B monoubiquitination is associated with enhanced proliferation and resistance to apoptosis in human lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4523.
Abstract 4537: Hexavalent chromium induces H4K16 hypoacetylation by NUPR1-mediated inactivation of histone acetyltransferase hMOF
Authors: Chen Qiao Yi , Zhang Xiaoru , Kluz Thomas , Costa Max , Sun Hong 
Published: July 2016

Abstract
Hexavalent chromium [Cr(VI)] is a well-established carcinogen linked to respiratory cancer and has been found at half of US toxic waste sites. In spite of considerable research efforts, the mechanism of Cr(VI)-induced carcinogenesis remains largely unknown. A growing body of evidence suggests that Cr is capable of inducing epigenetic changes, such as DNA methylation, histone modification, and microRNA. Acetylation of histone lysine residues neutralizes the positive charge from their side chains and decreases the affinity between histone tails and DNA, which subsequently leads to increased DNA accessibility and transcriptional activation in the gene promoter region. However, the effect of Cr(VI) on histone acetylation is still not clear. Here, we report that BEAS-2B cells exposed to 5 or 10 uM of Cr(VI) for 24 hours resulted in a striking and dose dependent decrease in H4K16ac. Co-treatment with Cr(VI) and Benzo(a)pyrene diolepoxide (BPDE) induced further decrease in H4K16ac. Cr (VI) transformed cells showed considerable decrease in H4K16ac compared to the control cells, which further indicates the correlation between Cr(VI) exposure and hypoacetylation of H4K16. H4K16 acetylation is known as an important determinant in higher-order chromatin structure and active gene expression. Male Absent on the First gene (MOF) is a H4K16 specific acetyltransferase. Our results indicate that Cr(VI) exposure significantly reduced MOF activity while its expression levels remained the same, thus suggesting that Cr(VI) may affect MOF activity rather than its expression. Moreover, Nuclear protein 1 (NUPR1), a MOF inhibitor, was increased in Cr(VI)-exposed cells. Depletion of NUPR1 in cells by small RNA interference rescued Cr(VI)- reduced H4K16ac. Together, our results indicate that Cr(VI) inhibits MOF activity through inducing NUPR1 expression which subsequently leads to H4K16 hypoacetylation. Since hypoacetylation of H4K16 is a known hallmark of human cancer, the results from our study presents strong evidence supporting the role of H4K16 hypoacetylation in chromium carcinogenesis.
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Citation Format: Qiao Yi Chen, Xiaoru Zhang, Thomas Kluz, Max Costa, Hong Sun. Hexavalent chromium induces H4K16 hypoacetylation by NUPR1-mediated inactivation of histone acetyltransferase hMOF. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4537.
Abstract 4544: FBW7 induces S-phase arrest caused by DNA double strand breaks through targeting SOX9 for proteasomal degradation
Authors: Hong Xuehui , Liu Wenyu , Song Ruipeng , Inuzuka Hiroyuki , Sabaawy Hatem E. , Morgan Katherine M. , Shah Jamie J. , Bunting Samuel F. , Feng Xing , Tsang Chi-Kwan , Shen Zhiyuan , Zheng X. F. Steven , Liu LianXin , Pine Sharon R. 
Published: July 2016

Abstract
SOX9 encodes a transcription factor that governs cell fate specification throughout development and tissue homeostasis. Elevated SOX9 is implicated in the genesis or progression of many human tumors through increasing cell proliferation and epithelial-mesenchymal transition. We observed that, in response to UV irradiation or certain chemotherapeutic agents, SOX9 is actively and rapidly degraded by a ubiquitin pathway dependent mechanism across several different tumor types including lung cancer, colon cancer, osteosarcoma and melanoma, as well as normal human bronchial epithelial cells. We found that SOX9 is phosphorylated by GSK3β at Ser-236, facilitating the direct binding and degradation of SOX9 via the F box protein, FBW7α. We also determined that the de-ubiquitinase, USP28, stabilizes SOX9 under normal conditions by sequestering FBW7, but is released from FBW7 after UV irradiation, allowing FBW7 to bind SOX9 and target it for destruction. DNA damage-induced SOX9 degradation was independent of p53, ATM, ATR and MAPK pathways. Failure to deplete SOX9 attenuated the DNA damage-induced intra-S-phase checkpoint and increased long-term cell survival. Moreover, mutations within the FBW7 phosphodegron binding site of SOX9 prevented SOX9 degradation after DNA damage, and incurred resistance of non-small cell lung cancer (NSCLC) cells to cisplatin in vivo. We found that cancer patients with tumors expressing high Sox9 and low Fbw7 levels exhibit inferior survival. Our discovery reveals a novel function of SOX9 in the cellular response to DNA damage. Induced degradation of SOX9 may be part of the protection mechanisms to maintain genomic stability. This new regulatory mechanism of the FBW7-SOX9 axis in cancer could have diagnostic and therapeutic implications.
Citation Format: Xuehui Hong, Wenyu Liu, Ruipeng Song, Hiroyuki Inuzuka, Hatem E. Sabaawy, Katherine M. Morgan, Jamie J. Shah, Samuel F. Bunting, Xing Feng, Chi-Kwan Tsang, Zhiyuan Shen, X. F. Steven Zheng, LianXin Liu, Sharon R. Pine. FBW7 induces S-phase arrest caused by DNA double strand breaks through targeting SOX9 for proteasomal degradation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4544.
Abstract 4548: High throughput siRNA screens uncover a high rate of USP8 and ESCRT pathway dependency in squamous carcinoma cell lines
Authors: Zhong Wendy , Cosgrove Elissa , Swearingen Elissa , Ollmann Mike , Banerjee Jayee , Watson Vivienne , Jaeckel Peter , Pfreimer Mariana , Materna-Reichelt Silvia , Beckmann Holger , Kassner Paul , Ruefli-Brasse Astrid , Nolan-Stevaux Olivier 
Published: July 2016

Abstract
USP8 and the ESCRT pathway (endosomal sorting complex required for transport) are required for cellular homeostasis through key functions in shuttling ubiquitinated proteins towards lysosomal degradation, and through regulating the maturation of autophagosomal structures. In large-scale siRNA screens, the vast majority of cancer cell lines do not demonstrate dependency on USP8 or ESCRT pathway components for viability. However, we identified three cell lines (HCC70, HCC1954 and PFSK1) that are acutely dependent on USP8 and other ESCRT components (HGS, TSG101) for viability. Using a transcriptome-wide association approach, we found that these three USP8-dependent cell lines also had in common the expression of SerpinB3, also known as SCCA1 (Squamous Cell Carcinoma Antigen 1). After selecting additional Squamous Cell Carcinoma cell lines for further validation of USP8-dependency by siRNA screening, we found that Squamous Carcinoma cell lines, irrespective of their SerpinB3 expression status, were far more likely to be dependent on USP8 for viability (23%; N = 22) than cancer cell lines of non-Squamous epithelial origin (4.5%; N = 67). To unravel possible molecular mechanisms underpinning the requirement of USP8 for the viability of USP8-dependent Squamous Carcinoma cell lines (including SCABER, BICR22, CALU1 and EBC1), we conducted additional transcriptome association studies and genetic interaction screens to uncover genes that are synthetic lethal with USP8 knock-down.
Citation Format: Wendy Zhong, Elissa Cosgrove, Elissa Swearingen, Mike Ollmann, Jayee Banerjee, Vivienne Watson, Peter Jaeckel, Mariana Pfreimer, Silvia Materna-Reichelt, Holger Beckmann, Paul Kassner, Astrid Ruefli-Brasse, Olivier Nolan-Stevaux. High throughput siRNA screens uncover a high rate of USP8 and ESCRT pathway dependency in squamous carcinoma cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4548.
Abstract 4553: Identification of CD30/TNFRSF8 as a primary target of the Myc oncoprotein and potential biomarker of Myc-driven cancer
Authors: Gennaro Victoria , Zhang Xiao-yong , DeSalle Lauren , Yu Duonan , Thomas-Tikhonenko Andrei , Vakoc Christopher , McMahon Steven B. 
Published: July 2016

Abstract
Pathological activation of the transcription factor Myc induces a multitude of human malignancies. In Myc-driven tumor progression, there is a robust dependence on Myc activity; however, strategies developed to explicitly modulate Myc function in cancer have yielded little clinical success. Patients harboring Myc-dependent tumors would benefit from a therapy that circumvents molecular targeting of Myc expression and instead directs against a distinct downstream effector.
Our preliminary data from an unbiased expression-profiling screen identify CD30 as a primary target of the Myc oncoprotein. CD30 is a member of the tumor necrosis factor superfamily and resides on the extracellular membrane; it is highly expressed in several lymphomas while acutely restricted in normal cells. Within the last few decades, CD30 has emerged as a diagnostic marker and therapeutic target of many lymphoproliferative diseases. However, the underlying mechanisms that regulate CD30 expression remain unclear. We report that CD30 is regulated at the transcriptional level by Myc. Through a genetic and biochemical approach, we define CD30 induction in a MYC-dependent manner across a variety of human cell lines of both lymphomagenic and non-lymphomagenic origin. Furthermore, deliberate modulation of Myc-activity demonstrates a positive correlation with CD30 surface protein expression in multiple malignancy models. With CD30 induction as a potential mechanism by which to identify and target Myc-driven oncogenesis, we can reshape detection and treatment of Myc-regulated cancer.
Citation Format: Victoria Gennaro, Xiao-yong Zhang, Lauren DeSalle, Duonan Yu, Andrei Thomas-Tikhonenko, Christopher Vakoc, Steven B. McMahon. Identification of CD30/TNFRSF8 as a primary target of the Myc oncoprotein and potential biomarker of Myc-driven cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4553.
Abstract 4567: Functional characterization of P58IPK-PERK pathway in prostate cancer cells
Authors: Sheng Xia , Storm Margrethe , Jin Yang , Saatcioglu Fahri 
Published: July 2016

Abstract
Androgen signaling is important for the normal development and function of the prostate as well as for prostate cancer (PCa). We recently found that androgens activated the IRE1α-XBP1 arm of the canonical unfolded protein response (UPR) pathways and simultaneously inhibited PERK-eIF2α signaling. Activation of the IRE1α-XBP1 arm was mediated by direct binding of the androgen receptor (AR) in the vicinity of IRE1, as well as XBP1s target genes, and increase in their expression. Consistently, AR and IRE1α pathway gene expression are correlated in human PCa samples and XBP1s protein expression is significantly increased in cancer compared to normal prostate. However, the mechanisms behind androgen mediated inhibition of PERK-eIF2α signaling are not clear at present. One possible mediator in this regard is P58IPK, an XBP1s target gene that can interact with and inhibit PERK and eIF2α phosphorylation. Here, we show that P58IPK expression is increased by androgens in a time-dependent manner and that it plays a pro-survival role in PCa cells. P58IPK knockdown activated PERK expression as well as subsequent eIF2α phosphorylation when induced with the UPR activator thapsigargin. These findings suggest that P58IPK mediates, at least in part, the differential androgen effects between the IRE1α and PERK signaling in PCa and may be a potential therapeutic target.
Citation Format: Xia Sheng, Margrethe Storm, Yang Jin, Fahri Saatcioglu. Functional characterization of P58IPK-PERK pathway in prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4567.
Abstract 4570: Decreased interleukin-17RA expression inhibits the tumorigenesis and independently predicts good prognosis of colorectal cancer patients
Authors: YANG CHIH-YUNG , Jiang Jeng-Kai 
Published: July 2016

Abstract
Background:
Interleukin-17 receptor type A (IL-17RA) plays critical role in promoting early colorectal tumor development and affects immune response in tumorigenesis. Our previous study have reported interleukin-17A modulated tumorigenesis and affected metastasis in colorectal cancers, but the roles of its receptor (IL-17R) in colorectal cancers remain unknown. This study explores potential role and function of IL-17RA in colorectal cancers.
Materials and Methods
The expression of IL-17RA was determined in colorectal cancer tissues and adjacent normal tissues using quantitative real-time PCR and immunohistochemistry. The IL-17RA expression level and clinical parameters were then analyzed. To investigate the functional significance of IL-17RA, IL-17RA knockdown cells were analyzed using transwell assay in vitro and implanted subcutaneously in mice, and monitored for primary tumor growth and angiogenesis.
Results
IL-17RA was overexpression in colorectal cancer tissues compared with adjacent normal tissues (P&lt;0.05).The elevated expression level of IL-17RA was associated with poor survival (P&lt;0.001). In vitro, the IL17RA knockdown cells reduced migration and invasion. In mice, the decreased IL-17RA inhibited tumor growth and angiogenesis.
Conclusions
These results demonstrated that IL-17RA plays a critical role in growth, angiogenesis and prognosis of colorectal cancer.
Citation Format: CHIH-YUNG YANG, Jeng-Kai Jiang. Decreased interleukin-17RA expression inhibits the tumorigenesis and independently predicts good prognosis of colorectal cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4570.