bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4546: Ubc9 sumoylation is required for its interaction with CDK6 through SUMO-interacting motif (SIM) and regulates CDK6 sumoylation in glioblastoma
Authors: Bellail Anita , Hao Chunhai 
Published: July 2016

Abstract
Small ubiquitin-like modifier-1 (SUMO1) is a conserved member of the ubiquitin-related protein family. Recently we have shown that the cell cycle G1 phase cyclin-dependent kinase-6 (CDK6) is modified by SUMO1 in glioblastoma (Bellail et al., Nat Commun. 2014). CDK6 sumoylation stabilizes CDK6 protein and its kinase activity and drives cell cycle progression for the cancer development and progression. SUMO1 is covalently attached to the Lysine 216 of the CDK6 protein through catalytic reactions by an E1 (SUMO-activating enzyme 1/2) and an E2-conjugating enzyme (UBC9). In this study, we further showed that UBC9 is phosphorylated by CDK1 kinase during mitosis and UBC9 phosphorylation increases the interaction of UBC9 with CDK6 and enhances SUMO1-CDK6 conjugation. Knockdown of SUMO1 by small hairpin RNA (shRNA) abolishes the interaction of UBC9 and CDK6 and SUMO1-CDK6 conjugation. UBC9 is conjugated by SUMO1 and recognizes its substrate protein through interaction of SUMO1 and SUMO-Interacting motif (SIMs) on the substrate protein. Indeed, the survey of CDK6 amino acid sequence and structure identified four SIMs on CDK6 protein. Each SIM was mutated to abrogate its binding property. Of the 4 SIMs, the CDK6-SIM4 is responsible for UBC9-CDK6 interaction as demonstrated by the finding that mutation of the first two amino-acids of the SIM sequence abolishes UBC9-CDK6 interaction and SUMO1-CDK6 conjugation. Our data show that UBC9 sumoylation is required for its interaction with CDK6 protein through SIM and thus involved in glioblastoma progression.
Citation Format: Anita Bellail, Chunhai Hao. Ubc9 sumoylation is required for its interaction with CDK6 through SUMO-interacting motif (SIM) and regulates CDK6 sumoylation in glioblastoma. [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 4546.
Abstract 4550: High-level nuclear GSK3β promotes glioma tumorigenesis by phosphorylating KDM1A and inducing its deubiquitination by USP22
Authors: Zhou Aidong , Lin Kangyu , Zhang Sicong , Huang Suyun 
Published: July 2016

Abstract
Glioblastoma multiforme (GBM) is the most lethal brain tumors and is resistant to most therapeutic endeavors. Glioma stem cells (GSCs) in GBM are responsible for glioma propagation and resistance to conventional therapies. GSK3β is a multifunctional serine/threonine kinase. Growing evidences have supported the oncogenic roles of GSK3β in diverse cancers, including in GBM; however, the functional mechanism of GSK3β in tumor initiation and propagation remains elusive. Our study showed that nuclear GSK3β is responsible for overexpression of the histone demethylase KDM1A and critically regulates histone H3K4 methylation during glioma tumorigenesis. GSK3β phosphorylates KDM1A, which induces its binding and deubiquitination by USP22, leading to KDM1A stabilization. GSK3β and USP22-dependent KDM1A stabilization is required for the demethylation of histone H3K4, thereby repression of BMP2, CDKN1A, and GATA6 transcription, and result in GSCs self-renewal and brain tumorigenesis. Moreover, introduction of a GSK3β-phosphorylation-mimic mutant KDM1A rescues the effect of GSK3β depletion on the inhibition of glioma tumorigenesis. In human glioblastoma specimens, KDM1A levels are correlated with nuclear GSK3β and USP22 levels. Furthermore, a GSK3 inhibitor tideglusib in a GBM mouse model inhibits the tumor initiating ability of GSCs, sensitizes tumors to temozolomide,
and prolongs mice survivals via KDM1A down-regulation. Our findings demonstrate that nuclear GSK3β and USP22-mediated KDM1A stabilization is essential for glioma tumorigenesis and highlights that targeting GSK3β as a therapeutic target for GBM.
Citation Format: Aidong Zhou, Kangyu Lin, Sicong Zhang, Suyun Huang. High-level nuclear GSK3β promotes glioma tumorigenesis by phosphorylating KDM1A and inducing its deubiquitination by USP22. [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 4550.
Abstract 4556: Activation of sonic hedgehog signaling is essential for non-alcoholic steatohepatitis induced by liver-specific disruption of Nrf1
Authors: Cao Mingnan , Guo Limei , Li Juan , Liu Chun , Zhang Yiguo , Yu Siwang , Kong Tony A-N. 
Published: July 2016

Abstract
Liver-specific inactivation of NF-E2 p45-related factor 1 (Nrf1) results in sequential development of non-alcoholic steatohepatitis (NASH), fibrosis, and finally hepatocellular carcinoma (HCC). However, the detailed mechanisms responsible for this phenotype remain uncertain. In the present study, a β-naphthoflavone (β-NF)-inducible liver-specific Nrf1 knockout mouse line which harbors an Nrf1flox/flox allele and a rat CYP1A1-Cre transgene was employed to investigate potential mechanism underlying Nrf1 deficiency-induced NASH.
β-NF-induced liver-specific knockout Nrf1 resulted in a reversible typical NASH and mild fibrosis phenotype. β-NF treatment almost abolished Nrf1 expression after 2 weeks, and induced dramatic elevation of serum transaminase, inflammation, necrosis, ballooning degeneration and HSC activation, but these phenotype diminished after 16 weeks, accompanied by restoration of Nrf1 expression. These observations clearly demonstrated the dependency of NASH and fibrosis on loss of Nrf1, and provide a novel model of reversible non-alcoholic liver diseases.
Notably, disruption of Nrf1 caused a sustained activation of sonic hedgehog (shh) signaling pathway accompanied by pronounced endoplasmic reticulum (ER) stress. More importantly, vismodegib, a hedgehog signaling inhibitor, dramatically reversed the deleterious effects caused by loss of Nrf1, such as elevation of serum transaminase activities, inflammatory cells infiltration and hepatocyte necrosis. It has been reported that hepatocytes undergoing endoplasmic reticulum stress and showed elevated expression of hedgehog ligands. However, the mRNA level of hedgehog ligand was not changed in Nrf1 deficiency mice, while the protein levels of both shh and Gli2 were significantly increased. Furthermore, chemical chaperone 4-PBA which can promote protein degradation partially reversed the effects of Nrf1 deficiency on shh signaling. Collectively, these data demonstrate that activation of sonic hedgehog signaling is essential for non-alcoholic steatohepatitis induced by liver-specific disruption of Nrf1, possibly through post-translational modification/procession of shh, and hedgehog signaling could be targeted to treat non-alcoholic liver diseases.
The present works were supported by the National Natural Science Foundation of China (No. 91429305, 81272468, and 81372266)
Citation Format: Mingnan Cao, Limei Guo, Juan Li, Chun Liu, Yiguo Zhang, Siwang Yu, Tony A-N. Kong. Activation of sonic hedgehog signaling is essential for non-alcoholic steatohepatitis induced by liver-specific disruption of Nrf1. [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 4556.
Abstract 4557: Tip110-mediated regulation of NF-κB activity is key to tumorigenesis
Authors: Timani Khalid Amine , Whitmill Amanda , Liu Ying , He Johnny J. 
Published: July 2016

Abstract
HIV-1 Tat-interacting protein (Tip110), also known as squamous cell carcinoma antigen recognized by T cells 3 (SART3), is a multifaceted nuclear protein and has been shown to function in tumor antigenicity. Tip110 protein expression is very low in normal tissues and non-proliferating cells but becomes highly elevated in a number of malignant tumor cell lines and cancerous tissues, pointing to its possible role in tumorigenesis. Our previous studies have shown that Tip110 specifically interacted with oncogenic deubiquitinating enzyme, USP15, and that ectopic expression of the Tip110 protein led to re-distribution of USP15 from the cytoplasm to the nucleus. USP15 is known to inhibit TNF-α-induced NF-κB activity by modulation of IκB-α ubiquitination. In the current study, we demonstrated that Tip110 augmented TNF-α-induced transcription activity of NF-κB, and that deletion of the nuclear localization domain in Tip110 obliterated the observed enhancement of TNF-α-induced NF-κB activity, providing the very first evidence to support the specific role of Tip110 in NF-κB activation. In addition, we found that Tip110 expression modulated IκB-α phosphorylation and that activation of NF-κB by Tip110 was mediated through the p38/MAPK pathway. Moreover, we showed that ectopic expression of Tip110 induced translocation of NF-κB p65 from the cytoplasm to the nucleus, reminiscent of the aforementioned translocation of USP15, in the absence of direct interaction of Tip110 with either p65 or IκB-α. Taken together, these results indicate that opposing regulation of TNFα-induced NF-κB activity by Tip110 and USP15 could be pivotal for modulation of tumorigenesis. Further delineation of the underlying signaling cascades will likely provide new insights into development of anti-tumor agents.
Citation Format: Khalid Amine Timani, Amanda Whitmill, Ying Liu, Johnny J. He. Tip110-mediated regulation of NF-κB activity is key to tumorigenesis. [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 4557.
Abstract 4558: PIN1 expression level is maintained by a negative feedback loop through regulation of Myc and miRNAs
Authors: Leong Ka Wai , Cheng Chi Wai , Kwong Yok Lam , Tse. Wai Choi Eric 
Published: July 2016

Abstract
Introduction: PIN1 is a peptidyl-prolyl-isomerase (PPIase) that binds specific motifs (serine/threonine preceding a proline) in proteins, thereby catalyzing cis/trans isomerization of the peptide bond between the phosphorylated serine/threonine and proline. As a result of such conformational changes, stability, sub-cellular localization, functional activity as well as protein-protein interactions of the PIN1-bound proteins may be altered. PIN1 has been demonstrated to play an important role in controlling various cellular processes such as cell proliferation, apoptosis and migration. Consequently, its expression has to be tightly controlled. Previously, we found that two miRNAs, miR-296-5p and miR-874-3p, served as negative regulators of PIN1. However, the mechanism regulating these two miRNAs remains to be defined.
Methods: The online database-UCSC Genome Bioinformatics (NCBI/hg18) was used to search for the upstream regulator of miR-296-5p and miR-874-3p. Luciferase reporter assay was conducted to examine the effect of the identified regulator on the promoter regions of miR-296 and miR-874-3p. Quantitative polymerase chain reaction (Q-PCR) was used to detect the expression levels of miR-296-5p and miR-874-3p. Protein expression levels of the identified regulator and PIN1 were examined by western immunoblotting.
Results: By screening the online database-UCSC, Myc was identified as a potential transcription factor for the miRNAs, miR-296-5p and miR-874-3p. As demonstrated by luciferase reporter assay, expression of Myc activated the promoters of miR-296-5p and miR-874-3p. Myc over-expression also increased the expression levels of these two miRNAs, which in turn led to down-regulation of PIN1. Interestingly, we found that over-expression of PIN1 increased the expression of Myc, miR-296-5p and miR-874-3p. We therefore hypothesized that PIN1 expression is maintained via a negative feedback loop of Myc-miRNAs-PIN1. Consistent with this hypothesis, we demonstrated that over-expression of exogenous EGFP-tagged PIN1 led to the enhancement of Myc, miR-296-5p and miR-874-3p expression, and thereby subsequently decrease the endogenous PIN1 level.
Conclusion: Taken together, our results suggested that the expression level of PIN1 is maintained by a negative feedback loop through the regulation of Myc, miR-296-5p and miR-874-3p.
Citation Format: Ka Wai Leong, Chi Wai Cheng, Yok Lam Kwong, Wai Choi Eric Tse. PIN1 expression level is maintained by a negative feedback loop through regulation of Myc and miRNAs. [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 4558.
Abstract 4562: Inhibition of STAT3 signaling in human liver cancer cells using Evista
Authors: Wang Yina , Zhao Chongqiang , Ma Haiyan , Li Huameng , Lu Jiagao , Li Chenglong , Lin Jiayuh , Lin Li 
Published: July 2016

Abstract
Liver cancer is one of the major causes of morbidity and mortality in China and also around the World. Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) signaling is frequently detected in human cancer including liver cancer and has emerged as a viable molecular target for liver cancer treatment. Novel therapeutic approaches of more effective treatments are much needed. To date, few STAT3 inhibitors are available for the therapy of liver cancer yet. Evista (Raloxifene HCI) is used for the prevention and treatment of osteoporosis and was approved for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer. We reported the discovery of Raloxifene as novel inhibitors of IL-6/GP130 protein­protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning. The possible effect of Evista in STAT3 signaling or liver cancer cells is still unclear. The ability of Evista to inhibit STAT3 was tested. Evista inhibited the P-STAT3 stimulated by IL-6 but not the induction of STAT1, STAT2, and STAT4 phosphorylation by IFN-α and IL-4. Evista inhibited STAT3 phosphorylation and resulted in the induction apoptosis on human liver cancer cell lines HEPG2, 7721, and HUH-7 as evidenced by caspase-3 cleavage. Evista also inhibited the cell viability, cell migration and colony formation in liver cancer cells. Furthermore, administration daily of Evista suppressed the HEPG2 tumor growth in mice in vivo. In summary, our study is the first report indicating that Evista also exhibits biology activity against persistent STAT3 signaling in human liver cancer cells. These results suggest that Evista may also be a chemoprevention agent for liver cancer by targeting persistent STAT3 signaling.
Citation Format: Yina Wang, Chongqiang Zhao, Haiyan Ma, Huameng Li, Jiagao Lu, Chenglong Li, Jiayuh Lin, Li Lin. Inhibition of STAT3 signaling in human liver cancer cells using Evista. [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 4562.
Abstract 4564: Elucidating the mechanism of the STAT3/NF-κB/EP4 signaling axis in pancreatic cancer
Authors: Munoz Amanda R. , Freeman James W. , Kumar Addanki P. 
Published: July 2016

Abstract
Despite recent advances to pancreatic cancer (PanCA) management, the 5 year survival rate remains only 7%. This poor survival rate highlights the importance of increasing our molecular understanding of PanCA pathogenesis to develop effective therapies to improve patient outcomes. We previously demonstrated that targeting the STAT3/NF-κB signaling axis with Nexrutine® (a Phellodendron amurense bark extract) was able to inhibit autophagy, ROS production, and proliferation in multiple PanCA cell lines. Our data also indicated the potential involvement of prostaglandin receptor EP4 in mediating these effects. To our surprise, we observed decreased levels of EP4 in human pancreatic tumors implicating a possible protective role. However, the mechanism behind STAT3/NF-κB signaling and its link to EP4 are still unknown. Using genetic and chemical inhibition of STAT3 and EP4, we have sought to define the STAT3/NF-κB/EP4 signaling axis. Our results indicate that inhibition of STAT3 via knockdown (STAT3 KD) using shRNA does not affect the proliferative ability or viability of PanCA cell lines when compared to non-transfected control (NTC) cells. Even though proliferation and viability were un-affected, STAT3 KD increased Cox-2 levels in a KRAS mutant cell line (Capan-2) and inhibited Cox-2 in a KRAS WT cell line (BxPC-3). Inhibition of EP4 increased STAT3 and NF-κB activity in KRAS mutant cell lines while decreasing activity in the KRAS WT cell line. Furthermore, EP4 inhibition increased protein levels of IL-6 and dual inhibition of STAT3 and EP4 yielded increased NF-κB activity and decreased Cox-2 levels. Converse experiments in cells treated with IL-6 revealed inhibited EP4 expression and decreased NF-κB activity. This may be the reason behind the increased STAT3 activity noted in EP4 inhibited KRAS mutant cells and supports the notion that EP4 may be protective against PanCA development. Taken together, these data suggests a feedback loop in regulating the STAT3/NF-κB/EP4 signaling cascade and that STAT3/NF-κB signaling axis members are differentially regulated upon STAT3 or EP4 inhibition possibly depending on KRAS status. Supported by Initiative for Maximizing Student Development (IMSD) Training Grant (R25 GM095480; NMJB), NCCIH (R01 AT007448; APK), and VA-MERIT Award (I01 BX 000766; APK)
Citation Format: Amanda R. Munoz, James W. Freeman, Addanki P. Kumar. Elucidating the mechanism of the STAT3/NF-κB/EP4 signaling axis in pancreatic 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 4564.
Abstract 4571: Semaphorin/plexin signalling promotes nucleocytoplasmic trafficking of nuclear receptors
Authors: Williamson Magali , Masters John R. 
Published: July 2016

Abstract
Androgen receptor (AR) signalling is critical to prostate cancer progression and androgen deprivation therapy (ADT) is the first line of treatment for metastatic prostate cancer. Acquired resistance to ADT results from androgen-independent reactivation of the AR pathway primarily. Prostate tumours also bypass androgen blockade by the upregulation of the glucocorticoid receptor (GR). Both AR and GR are nuclear receptors that bind their respective ligands in the cytoplasm and then translocate to the nucleus where they act as transcription factors. Plexins are cell surface receptors for semaphorins. PlexinB1 is overexpressed and mutated in several cancers including prostate cancer and deletion of the plexinB1 gene reduces metastasis in mouse models, indicating an oncogenic role for plexinB1 in prostate cancer.
We have found that activation of plexinB1 by semaphorin4D (Sema4D) results in AR phosphorylation at serine 81, activation of AR-transcriptional activity and increased expression of androgen-responsive genes, effects reversed by plexinB1 knockdown. PlexinB1 activation increases the translocation of both AR-GFP constructs and endogenous AR to the nucleus in prostate cancer cells. Furthermore knockdown of AR in the prostate cancer cell line LNCaP reduces Sema4D-induced anchorage-independent growth of these cells.
To determine if the Sema4D/plexinB1 signalling pathway also affects translocation of other nuclear receptors to the nucleus, we have also studied the effect of Sema4D treatment on nuclear trafficking of the glucocorticoid receptor (GR). Prostate cancer cells were transfected with a GR-GFP construct and the subcellular localisation of GR-GFP was monitored upon Sema4D treatment by immunocytochemistry and confocal microscopy. The nuclear translocation of endogenous GR was also assessed following Sema4D stimulation by immunocytochemistry and subcellular fractionation studies.
We found that activation of plexinB1 by Sema4D results in a significant increase in the percentage of cells with nuclear GR-GFP and in the nuclear localisation of endogenous GR in prostate cancer cells.
These findings show that plexinB1 activation has a role in the trafficking and activation of nuclear receptors and so may have a role in resistance to ADT in late stage prostate cancer.
Citation Format: Magali Williamson, John R. Masters. Semaphorin/plexin signalling promotes nucleocytoplasmic trafficking of nuclear receptors. [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 4571.
Abstract 4573: Complex interactions among different types of androgen receptor splice variants and the full-length androgen receptor in mediating castration resistance
Authors: Zhan Yang , Zhang Guanyi , Wang Xiaojie , Qi Yanfeng , Zhang Haitao , Dong Yan 
Published: July 2016

Abstract
Androgen receptor splice variants (AR-Vs) have been implicated in the pathogenesis and progression of castration-resistant prostate cancer after androgen-directed therapies. Approximately 20 AR-Vs have been identified to date. When expressed alone in cells, some AR-Vs (e.g., AR-V7 and ARv567es) localize primarily to the nucleus, whereas some others (e.g., AR-V4 and AR-V6) distribute equally between the nucleus and the cytoplasm. Significantly, the latter is often co-expressed with the nucleus-localized AR-Vs and the full-length AR (AR-FL). Thus, an important question that needs to be addressed is whether these different types of AR-Vs interact with each other as well as with AR-FL and the consequence of the interactions. In the present study, we used the bioluminescence resonance energy transfer (BRET) assay to show that both AR-V6 and AR-V4 can heterodimerize with AR-V7 and AR-FL. Consequently, AR-V7 and androgen-bound AR-FL induced nuclear localization of AR-V6 and AR-V4, leading to an increased ability of AR-V6 and AR-V4 to transactivate target genes and to confer castration-resistant cell growth. On the other hand, neither AR-V6 nor AR-V4 affected the subcellular localization of AR-V7 or AR-FL. These findings support the ability of AR-V7 and androgen-bound AR-FL to activate AR-V6 and AR-V4. Since AR-FL and nucleus-localized AR-Vs are the predominant forms of AR expressed in clinical specimens, it is likely that most of the AR-Vs in these cells are in the nucleus and are transcriptionally active. Our data therefore highlight the importance of the complex interactions among different AR-Vs and AR-FL in mediating castration resistance.
Citation Format: Yang Zhan, Guanyi Zhang, Xiaojie Wang, Yanfeng Qi, Haitao Zhang, Yan Dong. Complex interactions among different types of androgen receptor splice variants and the full-length androgen receptor in mediating castration resistance. [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 4573.