tbuckley/cabot-search huggingface dataset:
Abstract 2571: DBC1, a novel CBP-interacting protein, promotes p53 stability by regulating CBP-dependent p53 polyubiquitination
Authors: Oluwatoyin E. Akande, Priyadarshan K. Damle, Nicholas E. Sherman, Steven R. Grossman
Journal: Cancer Research (2017)

Abstract The acetyltransferase CBP, in conjunction with the E3 ubiquitin ligase enzyme, Mdm2, maintains physiologic levels of the tumor suppressor protein p53 in the absence of cellular stress, via a cytoplasmic, but not nuclear, p53-directed E4 polyubiquitin activity. CBP also possesses cytoplasmic, but not nuclear, E3 ubiquitin ligase, autoubiquitination activity. To understand the mechanism by which the ubiquitin ligase activities of CBP are compartmentalized in the cell, we have employed Multidimensional Protein Identification Technology (MudPIT) to identify cytoplasmic and nuclear CBP interacting proteins. MudPIT analysis revealed that Cell Cycle and Apoptosis Regulator protein (CCAR2), also known as Deleted in Breast Cancer 1 protein (DBC1), is a novel CBP- interacting protein in both the nucleus and cytoplasm. The N-terminus of DBC1 bound to multiple CBP domains, including the putative E3/E4 domain of CBP located at the N-terminus. Interaction between DBC1 and CBP suppressed the in vitro E3 autoubiquitination activity of CBP. Functional studies demonstrated that DBC1 directly regulates the cellular compartmentalization of CBP E3 and p53-directed E4 ubiquitin ligase activities. Knockdown of DBC1 in U2OS cells stimulated normally absent nuclear p53 polyubiquitination, and also caused a decrease in p53-dependent and p53-independent apoptosis, rescued by CBP/DBC1 double knockdown. Further, over-expression of DBC1 rescued the increase in nuclear p53 polyubiquitination and decrease in p53 half-life observed in DBC1 depleted cells. Together, these results identify DBC1 as a novel binding partner of CBP and a critical regulator of CBP ubiquitin ligase activities. Based on our data that DBC1 loss inactivates p53 function through destabilization, we queried the TCGA database for co-occurrence of DBC1 loss with maintenance of wild-type p53 status which showed that 33% of breast, 40% of lung, and 96% of prostate cancer cases with DBC1 alterations maintained wild-type p53 status. Therefore, by restoring DBC1 function, this work could lead to reactivation of p53 tumor suppressor activity in tumors with DBC1 alterations maintaining wild-type p53 status. Citation Format: Oluwatoyin E. Akande, Priyadarshan K. Damle, Nicholas E. Sherman, Steven R. Grossman. DBC1, a novel CBP-interacting protein, promotes p53 stability by regulating CBP-dependent p53 polyubiquitination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2571. doi:10.1158/1538-7445.AM2017-2571
Abstract 5377: Intragenic DNA methylation and increased gene expression: New directions from pan-cancer analysis
Authors: Michael H. McGuire, Shelley Herbrich, Sherry Wu, Ying Wang, Rajesha Rupaimoole, Hui Yao, Kshipra Gharpure, Gabriel Lopez-Berestein, Keith Baggerly, Anil Sood
Journal: Cancer Research (2017)

Abstract Purpose: While the impact of DNA methylation at the promoter region as a repressive influence is well-known, the vast majority of DNA methylation actually occurs outside of the promoter region. The function of intragenic DNA methylation remains incompletely understood. Here, we investigate how intragenic DNA methylation impacts gene expression, and how these modifications differ between normal and corresponding cancer tissues. Methods: A pan-cancer analysis of gene expression array data was integrated with Illumina 450k methylation array data across ten tumor types to produce correlation values between DNA methylation and gene expression at distinct loci on a genome-wide basis. The probes exhibiting a significant correlation between gene expression and DNA methylation were selected for further analysis. Results: We uncovered robust positive correlations between gene expression and 3’ methylation in 3,200 genes, with 590 genes in bladder cancer, and 256 genes in squamous cell lung carcinoma displaying a correlation coefficient of &amp;gt;0.5. Furthermore, we observed 44 genes with a correlation coefficient of &amp;gt;0.7 in at least two tissue types. The majority of genes with the strongest correlations are transcription factors known to play roles in differentiation and development, with an enrichment of zinc finger and homeobox-containing genes. Further analysis of these genes exhibit divergent 3’ methylation when comparing normal and tumor tissues. Importantly, the extent of 3’ methylation of these genes is associated with patient overall survival in 5 of the 10 tumor types analyzed, strongly suggesting that this process plays a role in cancer pathogenesis. Conclusion: DNA methylation of the 3’ region is a functionally and clinically relevant epigenetic modification, and may serve as a novel target for inhibiting tumorigenesis and tumor progression. Citation Format: Michael H. McGuire, Shelley Herbrich, Sherry Wu, Ying Wang, Rajesha Rupaimoole, Hui Yao, Kshipra Gharpure, Gabriel Lopez-Berestein, Keith Baggerly, Anil Sood. Intragenic DNA methylation and increased gene expression: New directions from pan-cancer analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5377. doi:10.1158/1538-7445.AM2017-5377
Abstract 2953: Tumor-associated macrophages infiltration highly associated with PD-L1 expression in gastric cancer
Authors: Kazuto Harada, Jeannelyn S Estrella, Arlene M Correa, Lang Ma, Xiaoquan Dong, Yan Xu, Wayne L Hofstette, Kazuki Sudo, Hisashi Onodera, Koyu Suzuki, Akihiro Suzuki, Randy L Johnson, Zhenning Zhenning, Shumei Song, Jaffer A Ajani, Hisashi Onodera
Journal: Cancer Research (2017)

Abstract Objectives: programmed death ligand 1 (PD-L1) is key protein for tumor to acquire the evacuation form T cell immune response and PD-L1 inhibitors are useful for an immune checkpoint blockade therapy. Tumor-associated macrophages (TAM) facilitate not only tumor cell progression, but also immunosuppression, which prevent tumor cell attack by T cell. Therefore, TAM is considered to be associated with PD-L1 expression, however it remain unclear in gastric cancer (GC). Methods: We performed immunohistochemical staining of PD-L1, CD68 (pan-macrophage) and CD163 (M2 macrophage) in 217 GC sample tissue microarray. The area of CD68 and CD163 positive cells were evaluated by using by the Cytoplasmic V2.0 algorithm on the Aperio ImageScope software. Results: 31 samples (14.3%) were positive for PD-L1 expression. The mean of rate for CD68 and CD163 positive area were 6.8±0.38% and 6.2±0.30%, respectively. CD163 positive macrophage infiltration is significantly more in diffuse type tumor than in intestinal type tumor (diffuse (n=111): 6.9%, intestinal (n=91): 5.3%, p=0.0056), but CD68 positive macrophage infiltration is similar in both type (p=0.38). Interestingly, PD-L1 expression tumor have significantly more CD68 and CD163 positive macrophage infiltration (CD68: PD-L1 negative 6.3%, positive 10.4%, p=0.0002, CD163: PD-L1 negative 5.7%, positive 9.2%, p&amp;lt;0.0001). PD-L1 expression and CD68 and CD163 positive area had no relationship between any clinicopathological features. Conclusions: Macrophages infiltration in GC is highly associated with PD-L1 expression of tumor cells. M2 macrophage infiltration is significantly associated with diffused type of GAC. This result suggests that TAM infiltration is associated with the immunosuppression through upregulating PD-L1 expression in GC cells. Thus, macrophages infiltration can serve as a potential therapeutic target. . Citation Format: Kazuto Harada, Jeannelyn S Estrella, Arlene M Correa, Lang Ma, Xiaoquan Dong, Yan Xu, Wayne L Hofstette, Kazuki Sudo, Hisashi Onodera, Koyu Suzuki, Akihiro Suzuki, Randy L Johnson, Zhenning Zhenning, Shumei Song, Jaffer A Ajani, Hisashi Onodera. Tumor-associated macrophages infiltration highly associated with PD-L1 expression in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2953. doi:10.1158/1538-7445.AM2017-2953
Abstract 284: The trending of lymph node dissection for esophageal squamous cell carcinoma over 40 years in China
Authors: Pei Nan Chen, Fu You Zhou, Hong Mei Chen, Xiao Shan Feng, Lei Sun, Ling Yuan, Ping He, Ying Pan, Tao Jiang, Min Jie Wu, Wen Jun Gao, Jin Chang Wei, Li Dong Wang
Journal: Cancer Research (2017)

Abstract The accumulated evidences have indicated the importance of lymph node dissection (LND) in improving survival for esophageal squamous cell carcinoma (ESCC). However, it is largely unclear in terms of standard lymph node dissection, e.g., how many is suitable and which node station is more important, etc. The present study was undertaken to summarize the trending of lymph node dissection for ESCC over 40 years at a single institute in northern China. A total of 27,260 ESCC patients were enrolled in this study from 1974 to 2016, including 16,565 males with a mean age of 59.72±7.82 and 10695 females with a mean age of 60.3±8.51. All the patients were from the ESCC database in Henan Key Laboratory for Esophageal Cancer Research of the First Affiliated Hospital, Zhengzhou University (1973-2016). All the patients had pathological LND records, including the number dissected. The patients were classified into four period groups based on the diagnosed time, group I (1974 to 1986, 367/1.3%), group II (1987 to 1996, 3182/11.7%), group III (1997 to 2006, 10, 494/38.5%) and group IV (2007 to 2016, 13,217/48.5%). The SPSS21.0 software was used to evaluate the trending changes of LND at different periods. The results showed that the total number of LND/the mean number by each patient from group I to group IV was 3,000/8.43, 22,001/7.07, 87,740/8.36, and 159,340/12.06, respectively (p&amp;lt;0.0001). Further analysis indicated that the total number of LND/the mean number by each patient from group I to group IV in males was 1,634/7.93, 13,428/6.99, 53,143/8.53 and 100,073/12.19, respectively and 1,366/8.48, 8,573/6.80, 34,597/8.11, 59,267/11.83, respectively in females. The present results indicate an apparent increasing in number of LND from 1987 to 2016 for esophageal cancer surgical treatment in China. Further analysis is needed to correlate the LND and metastasis and survival. [National High-Tech Research and Development Program of China (SQ2015AA0202183), Major Science and Technology Projects of Henan Province (161100311300).] Note: This abstract was not presented at the meeting. Citation Format: Pei Nan Chen, Fu You Zhou, Hong Mei Chen, Xiao Shan Feng, Lei Sun, Ling Yuan, Ping He, Ying Pan, Tao Jiang, Min Jie Wu, Wen Jun Gao, Jin Chang Wei, Li Dong Wang. The trending of lymph node dissection for esophageal squamous cell carcinoma over 40 years in China [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 284. doi:10.1158/1538-7445.AM2017-284
Abstract 4479: Cancer cell ribogenesis: MYC and the integrity of the RNA polymerase I-rRNA machinery
Authors: Stefano Rossetti, Andrzej J. Wierzbicki, Nicoletta Sacchi
Journal: Cancer Research (2017)

Abstract Upregulation of RNA Polymerase (Pol I)-mediated transcription of ribosomal RNA (rRNA) and increased ribogenesis, which are necessary to sustain the increased metabolic demand of highly proliferating cancer cells, are hallmarks of cancer. Increased rRNA transcription can be due deregulation of tumor suppressors and oncogenes that affect Pol I activity. Overexpression of the MYC oncogene, a potent Pol I activators, is particularly frequent in cancer. In addition, based on our analysis of the Cancer Genome Atlas (TCGA), amplification/upregulation of genes encoding for basal components of the Pol I transcriptional machinery is also frequent in cancers of various histotype (Rossetti et al., Cell Cycle, 2016). By using breast and ovarian epithelial cells, we mechanistically found that: 1) ectopic expression of either MYC or RRN3 (TIF-IA), a key Pol I basal component, by increasing rRNA synthesis, is sufficient to induce in vitro transformation phenotypes and to promote cell proliferation; 2) there is a causal link between MYC overexpression and RRN3 upregulation; 3) MYC- or RRN3-induced rRNA upregulation sensitizes cells to the anti-proliferative action of drugs inhibiting rRNA transcription. Our findings provide a rationale for using drugs targeting rRNA transcription to curb proliferation of cancers cells due to rRNA upregulation by MYC. Funding for this study was provided by an RPCI-UPCI Ovarian Cancer Spore DRP award (NS), the NCI R01 CA127614 grant (NS), the Terri Brodeur Breast Cancer Foundation (SR), the Susan Komen Foundation (SR), and the NCI P30 CA016056 institutional grant. Citation Format: Stefano Rossetti, Andrzej J. Wierzbicki, Nicoletta Sacchi. Cancer cell ribogenesis: MYC and the integrity of the RNA polymerase I-rRNA machinery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4479. doi:10.1158/1538-7445.AM2017-4479
Abstract 803: Targeting β-catenin/CBP signaling in OSCC
Authors: Khalid Alamoud, Khikmet Sadykov, Vinay Kartha, Stefano Monti, Anna Belkina, Jennifer Snyder-Cappione, Sara Pai, Maria Kukuruzinska
Journal: Cancer Research (2017)

Abstract Objectives: Oral squamous cell carcinoma (OSCC) is an aggressive malignancy characterized by molecular heterogeneity and locoregional spread associated with high morbidity. Aggressive cancers are thought to arise from populations of cancer initiating cells (CICs) that exhibit the properties of stem cells and drive tumor development, recurrence and resistance to therapy. The transcriptional regulator, β-catenin, has been implicated in OSCC CICs. Nuclear β-catenin has been shown to recruit the chromatin remodeling CREB binding protein (CBP) to drive expression of proliferation and survival genes, as well as genes that maintain stem-like phenotypes. We hypothesized that targeting β-catenin-CBP interaction will inhibit CICs in oral tumors and restore an epithelial phenotype. Methods: To test tumor aggressive potential of OSCC CICs, we used zebrafish as a model system. We isolated CD44+CD24hiCD29hi cells fom aggressive HSC-3 OSCC cells by FACS and assayed their ability to drive tumor growth and metastases in zebrafish compared to unsorted and CD44+CD24lowCD29low cells. In addition, we examined the role of the β-catenin/CBP axis in the aggressive phenotype of these cells. We also assessed whether the β-catenin/CBP axis affected CICs in tumors from immune competent HPV+ mice. Results: Zebrafish injected with subpopulation of cells co-expressing CD44+CD24hiCD2hi primitive cell surface markers drove rapid tumor growth and metastases, followed by unsorted and sorted CD44+CD24lowCD29low. Treatment of CD44+CD24hiCD29hi cells with a small molecule inhibitor of the β-catenin-CBP interaction, ICG-001, interfered with tumor growth and metastases in zebrafish. Further, ICG-001 inhibited tumor growth in immunocompetent HPV+ murine model. On a cellular level, ICG-001 promoted membrane localization of β-catenin, enhanced E-cadherin adhesion and restored epithelial phenotype. Significantly, ICG-001 gene signatures tracked with reduced overall patient survival in the cancer genome atlas, TCGA. Conclusion: Our studies indicate that the β-catenin/CBP axis promotes OSCC CICs and that ICG-001 may be an effective therapeutic agent for this malignancy. Support: Evans Center for Interdisciplinary Biomedical Research ARC funding AU 5303015 8000000. Citation Format: Khalid Alamoud, Khikmet Sadykov, Vinay Kartha, Stefano Monti, Anna Belkina, Jennifer Snyder-Cappione, Sara Pai, Maria Kukuruzinska. Targeting β-catenin/CBP signaling in OSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 803. doi:10.1158/1538-7445.AM2017-803
Abstract 5527: Effects of PTEN localization and phosphatase activity on gene expression profiling of glioblastoma cells
Authors: Yubing Wang, Andrew M. Chan
Journal: Cancer Research (2017)

Abstract PTEN possesses both protein and lipid phosphatase activities, with its tumor-suppressor function mainly depends on its lipid phosphatase activity through inhibiting the PI3K/AKT signaling pathway at the cell membrane. However, increasing evidence have demonstrated that PTEN also localizes to other intracellular organelles such as the endoplasmic reticulum, the mitochondria, or the nucleus where it plays important roles in multiple cellular processes. To further understand how PTEN localization affects the gene expression profiling in cancer cells, a PTEN null glioblastoma cell line, U87MG, was stably expressing wild-type, nuclear localization signal (NLS)-tagged, nuclear export signal (NES)-tagged and myristoylation (MYR)-tagged PTEN. Ion Torrent based whole transcriptome sequencing was used for gene expression analysis. Gene ontology enrichment analysis showed that the most common cellular component regulated by PTEN over-expression was extracellular factors, which function as growth factor-binding or fibronectin-binding molecules related to cell adhesion or organ system development. In contrast, nuclear PTEN promoted the enrichment of genes in collagen-binding and integrin-binding, which may be related to blood vessel development or cell motility. KEGG pathway enrichment also confirmed that PTEN over-expression upregulated focal adhesion pathway, an important pathway that frequently disrupted in PTEN Hamartoma Tumor Syndrome (PHTS). Moreover, nuclear PTEN differentially regulated genes showed higher enrichment in immune response signaling pathways. This unique gene expression profiling driven by NLS-PTEN indicated that besides the phosphatase activities, nuclear PTEN may have additional functions than merely inhibiting the PI3K signaling pathway. The transcriptome data showed potential downstream targets of PTEN in different subcellular localizations, which may lead to unique biological functions. More functional studies will be carried out to further validate how intracellular PTEN regulates the expression of these genes, and what are the signaling pathways involved in the regulatory processes. Funding sources - This work was supported by the Hong Kong PhD Fellowship (PF12-13876) to WY. AC was supported by a General Research Fund grant (#460713), a Collaborative Research Fund grant (C014-14G) from the Hong Kong University Grants Committee, a Lo Kwee-Seong Biomedical Research Seed Fund, and the Brain &amp; Mind Institute. Note: This abstract was not presented at the meeting. Citation Format: Yubing Wang, Andrew M. Chan. Effects of PTEN localization and phosphatase activity on gene expression profiling of glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5527. doi:10.1158/1538-7445.AM2017-5527
Abstract 1545: Loss of glycogen debranching enzyme (AGL) promotes rapid growth of non-small cell lung cancer cells
Authors: David R. Meier, Benjamin Weinhaus, Darby Oldenburg, Sunny Guin
Journal: Cancer Research (2017)

Abstract Glycogen Debranching Enzyme (AGL) is involved in glycogen breakdown. Compromise in glycogen breakdown due to loss of function mutations in the AGL gene lead to metabolic disease - Glycogen Storage Disease Type III. We have previously shown that loss of AGL results in rapid growth of bladder cancer cells using extensive in vitro and in vivo experiments. Here we test whether AGL regulate growth of non-small cell lung cancer (NSCLC) cells. We show that loss of AGL promotes rapid growth of NSCLC cells using anchorage independent growth assay. Loss of AGL also resulted in rapid xenograft growth of NSCLC cells when injected subcutaneously in immunocompromised mice. Whereas overexpression of AGL reduce the growth of these NSCLC cells. Further loss of glycogen phosphorylase the other enzyme involved in glycogen breakdown does not promote aggressive growth of these cancer cells. This observation is similar to our findings in bladder cancer which confirms that AGL regulates tumor growth independent of its role in glycogen metabolism. Thus using in vitro and in vivo experiments we show that AGL can regulate the growth of multiple tumor types such as bladder cancer and NSCLC. The exact mechanism on how AGL regulates NSCLC growth needs further investigation. Citation Format: David R. Meier, Benjamin Weinhaus, Darby Oldenburg, Sunny Guin. Loss of glycogen debranching enzyme (AGL) promotes rapid growth of non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1545. doi:10.1158/1538-7445.AM2017-1545