bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4308: Phosphatidic acid binds to ERK3 and stimulates phosphorylation of the ERK3 activation loop
Authors: Myers Amanda , Aldharee Hitham , Bedi Shimpi , Long Weiwen 
Published: August 2019

Abstract
Protein kinases modulate the activity of other proteins through phosphorylation and themselves are often regulated by phosphorylation of their activation loop. Extracellular signal-Regulated Kinase 3 (ERK3) is an atypical member of the ERK family of Mitogen-Activated Protein Kinases (MAPK), with a SerGlu-Gly (SEG) motif in its activation loop rather than the canonical Thr-Xaa-Tyr (TXY) motif of ERK1/2. Activation loop phosphorylation of ERK3 is not regulated by the signals known to activate ERK1/2, such as mitogenic growth factors. The cellular stimuli activating ERK3 kinase are virtually unknown. Some kinases, including mTOR and p21 activated kinase 1 and 2 (PAK1/2), are stimulated by binding to certain phospho-lipid signaling molecules, such as phosphatidic acids. Here, we show ERK3 binds to specific phospholipids in vitro, and the C-terminal domain may be important for this interaction. In addition, ERK3 can localize to the cell membrane. Further, phosphatidic acid stimulated phosphorylation of the activation loop in ERK3. Together, these results suggest that ERK3 kinase activity might be upregulated by specific phosphatidic acid species in cells.
Citation Format: Amanda Myers, Hitham Aldharee, Shimpi Bedi, Weiwen Long. Phosphatidic acid binds to ERK3 and stimulates phosphorylation of the ERK3 activation loop [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4308.
Abstract 4310: Targeting Wnt signaling pathway using curcumin in metatstatic breast cancer cell lines
Authors: Ma Nancy , Havard Patty , Shenoy Vinayak , Shenoy Anitha K. 
Published: August 2019

Abstract
Metastasis is the major reason for breast cancer-related deaths. The current treatment options for breast cancer include surgery, endocrine targeted therapy, radiation, chemotherapy and/or immunotherapy. However, even after treatment of the primary tumor at an early stage, breast cancer patients are at an increased risk of developing sudden metastases. Wnt signaling is a pivotal oncogenic pathway that contributes to human breast malignancy. High levels of Wnt ligands have been frequently detected in human breast cancers and accumulating evidence indicate a key role for the Wnt signaling pathway in the metastatic process. Curcumin, an active ingredient of turmeric has been shown to alter Wnt signaling as well as suppress metastasis in a variety of cancers. Here, we hypothesize that curcumin inhibits metastatic potential of breast cancer cell lines by targeting the Wnt signaling pathway. An initial dose dependent cytotoxic assay was performed with curcumin on two distinct breast cancer cell lines (epithelial and mesenchymal) to determine the optimum concentration for subsequent experiments. Our results indicate that curcumin imparts a dose dependent cytotoxic effect on both epithelial as well as mesenchymal breast cancer cell lines. Further, we observed that curcumin treatment alters the Wnt signaling pathway genes. Additional studies are warranted to confirm the effect of curcumin on Wnt signaling pathway and its role in combating proliferation and migration of breast cancer cells.
Citation Format: Nancy Ma, Patty Havard, Vinayak Shenoy, Anitha K. Shenoy. Targeting Wnt signaling pathway using curcumin in metatstatic breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4310.
Abstract 4314: Reduced m6A modification predicts malignant phenotypes and augmented tumorigenic signaling in gastric cancer
Authors: Zhang Cheng , Zhang Mengqi , Ge Sai , Lin Xiaotin , Huang Wenwen , Gan Ying , Gao Jing , Shen Lin 
Published: August 2019

Abstract
Purposes: As the most abundant epigenetic modification on mRNAs and long non-coding RNAs, N6-methyladenosine (m6A) extensively exists in mammalian cells. Controlled by writers (methyltransferases), readers (signal transducers) and erasers (demethylases), m6A influences mRNA structure, maturation and stability, thus regulating protein expression in a post-transcriptional manner. Nevertheless, current understandings to m6A’s pathological roles in tumorigenesis, especially in gastric cancer (GC) remain to be unveiled. In this study, by incorporating multiple datasets and in vitro experiments, we assessed m6A’s clinical-pathological relevance to GC and explored the underlying mechanisms.
Methods: The protein and mRNA expressions of canonical m6A regulators (METTL3/METTL14 as writers, YTHDF1/YTHDF2/YTHDF3 as readers and ALKBH5/FTO as erasers) were merged as signatures to indicate levels of m6A modification. Changes of clinical variables, mutations and molecules were assessed in patients with different m6A indications. Pathway and phenotype changes predicted to be affected by m6A were assessed in vitro with gastric cancer HGC27 and MG803 cell lines.
Results: We discovered that writers and readers were potential tumor suppressive, while erasers were potential oncogenic factors in GC. Low-m6A modification was an indication for adverse clinical outcomes and was correlated with specific cancer driving mutations, including CDH1, AR and GLI3. Oncogenic signaling and phenotypes were selectively enriched in m6A groups. Through in vitro experiments, we proved that reduced m6A (represented by METTL14 knockdown) promoted GC proliferation and invasiveness potentially through activating Wnt and PI3K-Akt signaling, while restored m6A (represented by FTO knockdown) reversed these phenotypical and molecular changes.
Conclusions: Our work demonstrated that m6A is a potential prognostic predictor in gastric cancer and further reveals the reduction of m6A activates oncogenic signaling and promotes gastric cancer malignancy.
Citation Format: Cheng Zhang, Mengqi Zhang, Sai Ge, Xiaotin Lin, Wenwen Huang, Ying Gan, Jing Gao, Lin Shen. Reduced m6A modification predicts malignant phenotypes and augmented tumorigenic signaling in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4314.
Abstract 4317: Application of gene methylation analysis for distinguishing primary tumor cells from normal epithelial cells from lung cancer patients in conditionally reprogrammed cell cultures
Authors: Wu Guodong , Xiao Yangui , Fang Fuyuan , Yao Da , Liu Ji , Cao Yanhua , Mao Yu , Yu Benjamin , Qian Youhui , Yu Derek 
Published: August 2019

Abstract
In vitro drug sensitivity assays utilizing “conditionally reprogrammed cells” (CRCs) from different primary tumor types to guide personalized therapy has been emerging. However, this approach has been hindered by the growth of normal epithelial cells in CRC cultures and the lack of effective biomarkers/assays to distinguish them from primary tumor cells. In this study, we developed a DNA methylation-based, real-time PCR assay to investigate the methylation status of SHOX2,PTGER4 and Septin9 gene promotor regions in human lung cancer formalin fixed paraffin-embedded (FFPE) samples. Our results showed increased DNA methylation for at least one of the three genes in 90% (28/31) of tumor samples as compared with the corresponding adjacent normal samples. Then we tested gene methylation in fresh surgical tumors versus normal adjacent tissues from lung cancer patients, and their respective in vitro CRC cultures. Increased methylation for at least one of the three genes was detected in 91.6% of tumor samples (11/12) as compared with the adjacent tissues, and these positive methylation statuses were maintained in 75% (9/12) of CRC cultures. Further results from in vitro assays showed a correlation between higher cell methylation status and increased growth property in 3D culture, as well as differential response to chemotherapy. Together, our results demonstrated that methylation of SHOX2, PTGER4 and Septin9 genes can be used as reliable biomarkers to monitor tumor cells in in vitro CRC cultures.
Citation Format: Guodong Wu, Yangui Xiao, Fuyuan Fang, Da Yao, Ji Liu, Yanhua Cao, Yu Mao, Benjamin Yu, Youhui Qian, Derek Yu. Application of gene methylation analysis for distinguishing primary tumor cells from normal epithelial cells from lung cancer patients in conditionally reprogrammed cell cultures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4317.
Abstract 4319: Hypoxia regulates m6A-reader YTHDF2 to fuel cancer-promoting inflammation in hepatocellular carcinoma
Authors: Hou Jiajie , Zhang He , Liu Jun , Zhao Zhenjun , Wang Jianye , Lu Zhike , Hu Bian , Zhou Jiankui , Zhao Zhicong , Feng Mingxuan , Zhang Haiyan , Shen Bin , Huang Xingxu , Sun Beicheng , Smyth Mark J. , He Chuan , Xia Qiang 
Published: August 2019

Abstract
Dynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous post-transcriptional regulation that affected mRNA homeostasis. However, the m6A-related epitranscriptomic alterations and functions remain elusive in human diseases such as cancer. Here we show that hypoxia regulates the ‘reader’ protein YTH domain family 2 (YTHDF2), to ultimately stabilize the methylated oncogene mRNAs in inflammation-associated hepatocellular carcinoma (HCC). YTHDF2 silenced in human HCC cells or depleted in mouse hepatocytes evoked pro-inflammatory responses and accelerated tumor growth and metastatic progression. Under hypoxia, YTHDF2 processed the decay of m6A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs, which were responsible for the inflammation-mediated malignancy. Reciprocally, YTHDF2 transcription succumbed to hypoxia-inducible factor-2α (HIF-2α). Administration of a HIF-2α antagonist (PT2385) restored YTHDF2-programed epigenetic machinery and repressed HCC progression. Hence, our findings provide a new insight into the mechanism by which hypoxia adapts m6A-mRNA editing to promote cancer.
Significance: We show that hypoxia induces downregulation of m6A-reader YTHDF2 and hyper-upregulation of m6A-mRNAs in human HCC, which adapts m6A decoration into a cancer-promoting mechanism. Thus we identify YTHDF2 as a suppressor in tumor growth and metastasis by targeting IL-11 and Serpin E2.
Note: This abstract was not presented at the meeting.
Citation Format: Jiajie Hou, He Zhang, Jun Liu, Zhenjun Zhao, Jianye Wang, Zhike Lu, Bian Hu, Jiankui Zhou, Zhicong Zhao, Mingxuan Feng, Haiyan Zhang, Bin Shen, Xingxu Huang, Beicheng Sun, Mark J. Smyth, Chuan He, Qiang Xia. Hypoxia regulates m6A-reader YTHDF2 to fuel cancer-promoting inflammation in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4319.
Abstract 4320: Enhanced expression of histone methyltransferases increase ERα expression in tamoxifen-resistant breast cancer cells
Authors: Kim Seungsu , Lee Min-Ho , Lee Mi-Ock 
Published: August 2019

Abstract
Estrogen receptor (ER)-positive breast cancers depend on ER signaling for growth and progression. Although tamoxifen remains the frontline treatment for such cancers, resistance to this drug limits its clinical efficacy. Nevertheless, the majority of tamoxifen-resistant patients retain ERα expression, providing a rationale for targeting ERα in these patients. Here, we found that the expression of mixed lineage leukemia (MLL) family proteins are increased in tamoxifen-resistant breast cancer cells and patients. Specifically, mixed lineage leukemia 3 (MLL3) and SET domain containing 1A (SET1A) depletion downregulated the expression of ERα protein and mRNA levels in a ER-positive breast cancer cell. Chromatin Immunoprecipitation analysis revealed that the knock-down of MLL3 and SET1A reduce the histone H3K4 methylation status in ESR1 promoter regions. We also observed the positive correlation between ERα level and MLL3/SET1A level in breast cancer clinical data sets. Importantly, MLL3 and SET1A depletion downregulated the ERα and its downstream growth-related protein levels, as well as the growth of both ER-positive and tamoxifen-resistant breast cancer cells. Likewise, MLL3 and SET1A knockdown decreased the proportion of cells entering the cell cycle. Additional fulvestrant treatment resulted in synergistic reduction of ERα levels and growth of the tamoxifen-resistant breast cancer cells. Thus, enhanced expression of MLL3 and SET1A in tamoxifen-resistant breast cancer cells supported ERα-dependent growth of breast cancer cells, suggesting that MLL3 SET1A might provide an attractive target for overcoming endocrine resistance.
Citation Format: Seungsu Kim, Min-Ho Lee, Mi-Ock Lee. Enhanced expression of histone methyltransferases increase ERα expression in tamoxifen-resistant breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4320.
Abstract 4321: Epigenetic regulation of TP73 expression in HCC and GI cancer
Authors: Yao Zhixing , Poto Cristina Di , Ressom Habtom W. , Sherif Zaki A. 
Published: August 2019

Abstract
Tumorigenesis results from an accumulation of mutational and epigenetic changes that alter normal cell growth and survival pathways. TP73 is the homologue of the master tumor suppressor TP53 involved in cellular responses to stress and development. The TP73 gene encodes two different protein isoforms, TAp73 and ΔNp73, and maps to a region on chromosome 1p36 that is frequently deleted in neuroblastoma and other tumors, and is thought to contain multiple tumor suppressor genes. However, the analysis of p73-knockout mice yielded conflicting results with respect to tumor suppression. World-wide efforts in sequencing the TP73 gene in patient tumor samples have not provided evidence for genetic alterations as a common cause of TP73 inactivation in human cancer. The role of TP73 in tumorigenesis has remained elusive to date. In this study, we isolated two stem cell lines from normal young and old human liver tissues to determine TP73 expression in normal human liver stem cell and hepatocellular cancer (HCC) cell lines (HepG2, SNU398, SNU449 & SNU475), gastrointestinal cancer (GI) cell lines (Caco2 & HCT116) and a normal skin fibroblast cell line (HS27). The results show that TP73 only expresses in cancer cell lines. Further immunohistochemistry studies on human normal liver tissues as well as adjacent normal and cancerous liver tissues from HCC patients confirm that TP73 only expresses in the cancerous tissues. Moreover, methylation-specific PCR and bisulfite sequencing studies revealed that TP73 promoter is activated only in cancer cell lines by DNA methylation. Furthermore, ChIP assay results demonstrated that CTCF (a chromosomal networking protein CCCTC binding factor) binds to TP73 promoter and regulates TP73 expression. Our observation may prove significant for the development of future therapeutic and diagnostic applications.
Citation Format: Zhixing Yao, Cristina Di Poto, Habtom W. Ressom, Zaki A. Sherif. Epigenetic regulation of TP73 expression in HCC and GI cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4321.
Abstract 4333: GCN5 positively correlates with c-MYC in non-small cell lung cancer
Authors: Mustachio Lisa Maria , Roszik Jason , Farria Aimee , Dent Sharon YR 
Published: August 2019

Abstract
Lung cancer causes the highest mortality in cancer-related deaths. Definition of novel molecular targets is needed since these cancers often become resistant to existing therapies. Epigenetic modifications may provide such targets. Recent reports suggest that the histone acetyltransferase (HAT) module within the transcriptional coactivator SAGA complex plays a role in cancer, creating a new link between epigenetic regulators and this disease. We aim to define the role of the SAGA HAT protein GCN5 in the regulation and function of oncogenes in lung cancers. Since prior work indicates that GCN5 regulates the stability of c-MYC and serves as a coactivator for MYC target genes, we hypothesize that there is a positive relationship between GCN5 and c-MYC in non-small cell lung cancer (NSCLC). We also propose that inhibition of GCN5 will reduce lung cancer formation and progression in mouse models of lung cancer driven by c-MYC overexpression. Our data indicate that both GCN5 and c-MYC proteins are upregulated in NSCLC cells compared to normal lung epithelial cell lines. This trend is observable only at the protein level, indicating that the upregulation of these proteins in NSCLC cells occurs post-transcriptionally. Both GCN5 and c-MYC expression levels are also positively associated in mouse and human NSCLC cell lines. Genetic repression of GCN5 in NSCLC cells reduces cell proliferation, increases the population of necrotic cells, and reduces c-MYC expression. Inhibition of the GCN5 active site using commercially available probes in NSCLC cells significantly (p &lt; 0.05) reduces cell proliferation, increases the percentage of cells undergoing apoptosis, and reduces c-MYC expression. In human NSCLC tissues, GCN5 and c-MYC positively correlate and are associated with MYC target genes. Our ongoing studies will determine whether targeting GCN5 represses multiple oncogenic pathways in cancer and whether it inhibits oncoproteins difficult to directly target, such as MYC. We expect that our findings will highlight the importance of epigenetic regulators in carcinogenesis and extend beyond our current research focus to other cancer types.
Citation Format: Lisa Maria Mustachio, Jason Roszik, Aimee Farria, Sharon YR Dent. GCN5 positively correlates with c-MYC in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4333.
Abstract 4334: Epigenetic reprogramming of tissue-specific transcription promotes metastasis
Authors: Teng Shuaishuai , Li Yang , Yang Ming , Qi Rui , Wang Qianyu , Lu Zhi , Wang Dong 
Published: August 2019

Abstract
Metastasis is the cause of death for 90% of cancer patients, but little is known about how cancer cells adapt to and colonize new tissue environments. Colorectal cancer (CRC) is the third most common cancer and the fourth most common cancer cause of death globally. Here, we investigated how metastatic cancer cells, such as CRC cells, with original-tissue specificity adapt to the environment of a distant tissue, like liver.
By analyzing transcriptome data of multiple cohorts of clinical samples and primary/metastatic cell lines, we found metastatic CRC cells lose their colon-specific gene transcription program and gain a liver-specific gene transcription program as they metastasize in the liver. The elevated expression of a number of liver-specific genes was confirmed in human liver metastatic tumors by immunohistochemistry. Through epigenomic profiling, we revealed this transcription reprogramming is driven by a reshaped epigenetic landscape of both typical and super-enhancers, and chemical inhibition of enhancer activity disrupts the ability of cells to execute this altered transcription program and consequently inhibits metastasis. Further we identified liver-specific transcription factors, FOXA2 and HNF1A, bind to the gained enhancers in liver metastatic cells and activate the expression of liver-specific genes. We also found both FOXA2 and HNF1A are highly expressed in human liver metastatic tumors compared to primary CRC tumors. Loss of function of FOXA2 or HNF1A inhibits liver-specific transcription and impairs the ability of metastatic CRC cells to adapt to liver. Consistently, the gain of function of HNF1A activated liver-specific transcription and enhanced CRC liver metastasis.
Our findings indicate the direct contribution of a reprogrammed tissue-specific transcription program, which is induced by reshaped epigenetic landscape as well as distant-tissue-specific transcription factors, to the adaption and colonization of metastatic CRC cells to a distal organ. Notably, in addition to CRC liver metastasis, this tissue-specific transcription reprogramming is also observed in other multiple distant organs and/or cancer types. In summary, our data suggest that epigenetically reprogrammed tissue-specific transcription promotes metastasis and might have implications for targeted anti-metastasis therapies.
Citation Format: Shuaishuai Teng, Yang Li, Ming Yang, Rui Qi, Qianyu Wang, Zhi Lu, Dong Wang. Epigenetic reprogramming of tissue-specific transcription promotes metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4334.