45 results on '"Victor X. Jin"'
Search Results
2. Data from Interferon-Stimulated Genes Are Transcriptionally Repressed by PR in Breast Cancer
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Christy R. Hagan, Geoffrey L. Greene, Victor X. Jin, Katelin A. Gibson, Gloria M. Trinca, Sean M. Holloran, Tianbao Li, Jade A. Hall, Hari Singhal, Merit L. Goodman, and Katherine R. Walter
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The progesterone receptor (PR) regulates transcriptional programs that drive proliferation, survival, and stem cell phenotypes. Although the role of native progesterone in the development of breast cancer remains controversial, PR clearly alters the transcriptome in breast tumors. This study identifies a class of genes, Interferon (IFN)-stimulated genes (ISGs), potently downregulated by ligand-activated PR which have not been previously shown to be regulated by PR. Progestin-dependent transcriptional repression of ISGs was observed in breast cancer cell line models and human breast tumors. Ligand-independent regulation of ISGs was also observed, as basal transcript levels were markedly higher in cells with PR knockdown. PR repressed ISG transcription in response to IFN treatment, the canonical mechanism through which these genes are activated. Liganded PR is robustly recruited to enhancer regions of ISGs, and ISG transcriptional repression is dependent upon PR's ability to bind DNA. In response to PR activation, key regulatory transcription factors that are required for IFN-activated ISG transcription, STAT2 and IRF9, exhibit impaired recruitment to ISG promoter regions, correlating with PR/ligand-dependent ISG transcriptional repression. IFN activation is a critical early step in nascent tumor recognition and destruction through immunosurveillance. As the large majority of breast tumors are PR positive at the time of diagnosis, PR-dependent downregulation of IFN signaling may be a mechanism through which early PR-positive breast tumors evade the immune system and develop into clinically relevant tumors.Implications: This study highlights a novel transcriptional mechanism through which PR drives breast cancer development and potentially evades the immune system. Mol Cancer Res; 15(10); 1331–40. ©2017 AACR.
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- 2023
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3. Supplementary Figure from EpCAM-Regulated Transcription Exerts Influences on Nanomechanical Properties of Endometrial Cancer Cells That Promote Epithelial-to-Mesenchymal Transition
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Tim Hui-Ming Huang, Maria E. Gaczynska, Nameer B. Kirma, Victor X. Jin, Jianhua Ruan, Lu Liu, Yi-Wen Huang, Yao Wang, Pawel Osmulski, and Ya-Ting Hsu
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Supplementary Figure S1 Expression of EpCAM, LEF1 in human endometrial cancer patients, cancer cell lines and mouse endometrial tissues. Supplementary Figure S2 Quantification of EpEX immunofluorescence staining and EGFR expression in endometrial cancer cell lines. Supplementary Figure S3 Summary of ChIP-seq of EpICD in RL95-2 cells. Supplementary Figure S4 Overview of ChIP-seq of LEF1 in RL95-2 cells. Supplementary Figure S5 Pathway enrichment analysis unique/shared TSS-bound genes in 12 and 24 hours EGF. Supplementary Figure S6 105 EpICD-LEF1-TSS gene expression profiles in UCEC (Uterine Corpus Endometrial Carcinoma) patients and normal control samples in TCGA cohort. Supplementary Figure S7 EpCAM-edited cells showed reduced EGF-stimulated gene activation. Supplementary Figure S8 RL95-2 cells showed no apoptosis and cytoskeleton content induced by EGF treatments in RL95-2 and EpCAM-edited clone. Supplementary Figure S9 EpCAM molecules were detected with recognition AFM only on cells expressing this protein.
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- 2023
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4. Data from MicroRNA-31 Predicts the Presence of Lymph Node Metastases and Survival in Patients with Lung Adenocarcinoma
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Tim Lautenschlaeger, Victor X. Jin, Arnab Chakravarti, Carlo M. Croce, Patrick Ross, Leona W. Ayers, Sung-Suk Suh, Taewan Kim, Hiroshi Nakanishi, Stefano Volinia, Bin Li, Yao Wang, Alexander Huebner, Vaia Dedousi-Huebner, James Perry, Ri Cui, Zhenqing Ye, and Wei Meng
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Purpose: We conducted genome-wide miRNA-sequencing (miRNA-seq) in primary cancer tissue from patients of lung adenocarcinoma to identify markers for the presence of lymph node metastasis.Experimental Design: Markers for lymph node metastasis identified by sequencing were validated in a separate cohort using quantitative PCR. After additional validation in the The Cancer Genome Atlas (TCGA) dataset, functional characterization studies were conducted in vitro.Results: MiR-31 was upregulated in lung adenocarcinoma tissues from patients with lymph node metastases compared with those without lymph node metastases. We confirmed miR-31 to be upregulated in lymph node-positive patients in a separate patient cohort (P = 0.009, t test), and to be expressed at higher levels in adenocarcinoma tissue than in matched normal adjacent lung tissues (P < 0.0001, paired t test). MiR-31 was then validated as a marker for lymph node metastasis in an external validation cohort of 233 lung adenocarcinoma cases of the TCGA (P = 0.031, t test). In vitro functional assays showed that miR-31 increases cell migration, invasion, and proliferation in an ERK1/2 signaling-dependent manner. Notably, miR-31 was a significant predictor of survival in a multivariate cox regression model even when controlling for cancer staging. Exploratory in silico analysis showed that low expression of miR-31 is associated with excellent survival for T2N0 patients.Conclusions: We applied miRNA-seq to study microRNomes in lung adenocarcinoma tissue samples for the first time and potentially identified a miRNA predicting the presence of lymph node metastasis and survival outcomes in patients of lung adenocarcinoma. Clin Cancer Res; 19(19); 5423–33. ©2013 AACR.
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- 2023
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5. Supplementary Tables from MicroRNA-31 Predicts the Presence of Lymph Node Metastases and Survival in Patients with Lung Adenocarcinoma
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Tim Lautenschlaeger, Victor X. Jin, Arnab Chakravarti, Carlo M. Croce, Patrick Ross, Leona W. Ayers, Sung-Suk Suh, Taewan Kim, Hiroshi Nakanishi, Stefano Volinia, Bin Li, Yao Wang, Alexander Huebner, Vaia Dedousi-Huebner, James Perry, Ri Cui, Zhenqing Ye, and Wei Meng
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PDF file, 34K, Supplementary Table 1. Clinical demographic information of 43 lung ADC cases. NAT is normal adjacent tissue. Supplementary Table 2. Clinical demographic information of lung adenocarcinoma TCGA patients. Supplementary Table 3. IPA analysis for the downstream targets for miR-31. Supplementary Table 4. Genetic alteration overview of the cell lines used in this study. Supplementary Table 5. Correlation coefficient between EMT-related genes and miR-31 expression.
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- 2023
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6. Supplementary Table S2 from Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle–Related Transcription and Attenuated Androgen Response
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Tim H.-M. Huang, Chun-Liang Chen, Victor X. Jin, Qianben Wang, Wei-Ting Chao, Zhijie Liu, LuZhe Sun, Addanki P. Kumar, Michael A. Liss, Nameer B. Kirma, Chun-Lin Lin, Chiou-Miin Wang, Chia-Nung Hung, Rohit R. Jadhav, Anna D. Louie, Che-Kuang Lin, Yao Wang, and Aaron M. Horning
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Supplementary Table S2: qPCR primer for subcluster E genes
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- 2023
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7. Supplementary Table S1 from Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle–Related Transcription and Attenuated Androgen Response
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Tim H.-M. Huang, Chun-Liang Chen, Victor X. Jin, Qianben Wang, Wei-Ting Chao, Zhijie Liu, LuZhe Sun, Addanki P. Kumar, Michael A. Liss, Nameer B. Kirma, Chun-Lin Lin, Chiou-Miin Wang, Chia-Nung Hung, Rohit R. Jadhav, Anna D. Louie, Che-Kuang Lin, Yao Wang, and Aaron M. Horning
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Supplementary Table S1: qPCR Primers for androgen responsive genes
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- 2023
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8. Data from EpCAM-Regulated Transcription Exerts Influences on Nanomechanical Properties of Endometrial Cancer Cells That Promote Epithelial-to-Mesenchymal Transition
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Tim Hui-Ming Huang, Maria E. Gaczynska, Nameer B. Kirma, Victor X. Jin, Jianhua Ruan, Lu Liu, Yi-Wen Huang, Yao Wang, Pawel Osmulski, and Ya-Ting Hsu
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Overexpression of epithelial cell adhesion molecule (EpCAM) has been implicated in advanced endometrial cancer, but its roles in this progression remain to be elucidated. In addition to its structural role in modulating cell-surface adhesion, here we demonstrate that EpCAM is a regulatory molecule in which its internalization into the nucleus turns on a transcription program. Activation of EGF/EGFR signal transduction triggered cell-surface cleavage of EpCAM, leading to nuclear internalization of its cytoplasmic domain EpICD. ChIP-seq analysis identified target genes that are coregulated by EpICD and its transcription partner, LEF-1. Network enrichment analysis further uncovered a group of 105 genes encoding functions for tight junction, adherent, and cell migration. Furthermore, nanomechanical analysis by atomic force microscopy revealed increased softness and decreased adhesiveness of EGF-stimulated cancer cells, implicating acquisition of an epithelial–mesenchymal transition (EMT) phenotype. Thus, genome editing of EpCAM could be associated with altering these nanomechanical properties towards a less aggressive phenotype. Using this integrative genomic–biophysical approach, we demonstrate for the first time an intricate relationship between EpCAM-regulated transcription and altered biophysical properties of cells that promote EMT in advanced endometrial cancer. Cancer Res; 76(21); 6171–82. ©2016 AACR.
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- 2023
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9. Supplementary Table S4 from Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle–Related Transcription and Attenuated Androgen Response
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Tim H.-M. Huang, Chun-Liang Chen, Victor X. Jin, Qianben Wang, Wei-Ting Chao, Zhijie Liu, LuZhe Sun, Addanki P. Kumar, Michael A. Liss, Nameer B. Kirma, Chun-Lin Lin, Chiou-Miin Wang, Chia-Nung Hung, Rohit R. Jadhav, Anna D. Louie, Che-Kuang Lin, Yao Wang, and Aaron M. Horning
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Supplementary Table S4: List of genes most highly associated with each subcluster
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- 2023
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10. Supplementary Figure Legends from EpCAM-Regulated Transcription Exerts Influences on Nanomechanical Properties of Endometrial Cancer Cells That Promote Epithelial-to-Mesenchymal Transition
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Tim Hui-Ming Huang, Maria E. Gaczynska, Nameer B. Kirma, Victor X. Jin, Jianhua Ruan, Lu Liu, Yi-Wen Huang, Yao Wang, Pawel Osmulski, and Ya-Ting Hsu
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Supplementary Figure Legends Fig S1-S9
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- 2023
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11. Data from Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle–Related Transcription and Attenuated Androgen Response
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Tim H.-M. Huang, Chun-Liang Chen, Victor X. Jin, Qianben Wang, Wei-Ting Chao, Zhijie Liu, LuZhe Sun, Addanki P. Kumar, Michael A. Liss, Nameer B. Kirma, Chun-Lin Lin, Chiou-Miin Wang, Chia-Nung Hung, Rohit R. Jadhav, Anna D. Louie, Che-Kuang Lin, Yao Wang, and Aaron M. Horning
- Abstract
Increasing evidence suggests the presence of minor cell subpopulations in prostate cancer that are androgen independent and poised for selection as dominant clones after androgen deprivation therapy. In this study, we investigated this phenomenon by stratifying cell subpopulations based on transcriptome profiling of 144 single LNCaP prostate cancer cells treated or untreated with androgen after cell-cycle synchronization. Model-based clustering of 397 differentially expressed genes identified eight potential subpopulations of LNCaP cells, revealing a previously unappreciable level of cellular heterogeneity to androgen stimulation. One subpopulation displayed stem-like features with a slower cell doubling rate, increased sphere formation capability, and resistance to G2–M arrest induced by a mitosis inhibitor. Advanced growth of this subpopulation was associated with enhanced expression of 10 cell-cycle–related genes (CCNB2, DLGAP5, CENPF, CENPE, MKI67, PTTG1, CDC20, PLK1, HMMR, and CCNB1) and decreased dependence upon androgen receptor signaling. In silico analysis of RNA-seq data from The Cancer Genome Atlas further demonstrated that concordant upregulation of these genes was linked to recurrent prostate cancers. Analysis of receiver operating characteristic curves implicates aberrant expression of these genes and could be useful for early identification of tumors that subsequently develop biochemical recurrence. Moreover, this single-cell approach provides a better understanding of how prostate cancer cells respond heterogeneously to androgen deprivation therapies and reveals characteristics of subpopulations resistant to this treatment.Significance: Illustrating the challenge in treating cancers with targeted drugs, which by selecting for drug resistance can drive metastatic progression, this study characterized the plasticity and heterogeneity of prostate cancer cells with regard to androgen dependence, defining the character or minor subpopulations of androgen-independent cells that are poised for clonal selection after androgen-deprivation therapy. Cancer Res; 78(4); 853–64. ©2017 AACR.
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- 2023
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12. Supplementary Figure S1-10 from Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle–Related Transcription and Attenuated Androgen Response
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Tim H.-M. Huang, Chun-Liang Chen, Victor X. Jin, Qianben Wang, Wei-Ting Chao, Zhijie Liu, LuZhe Sun, Addanki P. Kumar, Michael A. Liss, Nameer B. Kirma, Chun-Lin Lin, Chiou-Miin Wang, Chia-Nung Hung, Rohit R. Jadhav, Anna D. Louie, Che-Kuang Lin, Yao Wang, and Aaron M. Horning
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Supplementary Figure S1: Time-course expression analysis of LNCaP cells reveals dynamic and heterogeneous responses to androgen stimulation. Supplementary Figure S2: Cell cycle progression of LNCaP cells treated with or without R1881 after cell synchronization by double thymidine block (DTB). Supplementary Figure S3: The summary of aligned and unaligned single-cell RNA-seq reads counts. Supplementary Figure S4: Correlation of single-cell RNA-seq ensemble reads with representative bulk RNA-seq reads. Supplementary Figure S5: Venn diagrams illustrating the comparison of differentially expressed genes found in single- and bulk-cell LNCaP experiments. Supplementary Figure S6: The Mclust algorithm defines likely subgroups using a "model-based" approach. Supplementary Figure S7: Each cell within each subcluster exhibits a similar gene expression profile. Supplementary Figure S8: Gleason score and biochemical recurrence status compared to each subcluster''s gene expression profile. Supplementary Figure S9: Differential expression of 10 genes in LNCaP''s 8.1 subpopulation of cells. Supplementary Figure S10: High single-cell expression of 10 genes in PC3 similar to 12hr-R1881 LNCaP cells.
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- 2023
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13. Supplementary Figures from MicroRNA-31 Predicts the Presence of Lymph Node Metastases and Survival in Patients with Lung Adenocarcinoma
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Tim Lautenschlaeger, Victor X. Jin, Arnab Chakravarti, Carlo M. Croce, Patrick Ross, Leona W. Ayers, Sung-Suk Suh, Taewan Kim, Hiroshi Nakanishi, Stefano Volinia, Bin Li, Yao Wang, Alexander Huebner, Vaia Dedousi-Huebner, James Perry, Ri Cui, Zhenqing Ye, and Wei Meng
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PDF file, 450K, Supplementary Figure 1. The length distribution of reads for ten miR-seq samples Supplementary Figure 2. Flow diagram illustrating microRNA quantification techniques used and sample sizes of each step of the analysis. NAT: normal adjacent tissue. Supplemental Figure 3. Identification of differentially expressed miRNAs between N0 and N1+ groups of patients. Supplementary Figure 4. The receiver operator characteristic (ROC) curve as well as area under curve (AUC) was determined using CART. The results show that AUC is 0.79 in 43 lung ADC samples (cohort 1 +2). Supplementary Figure 5. Higher miR-31 expression is associated with adverse outcome in T2N0 patients (n=75, log-rank p=0.0194) Supplementary Figure 6. IPA showing the top five canonical pathways for miR-31 target genes is the CDK5 (A), PTEN (B), p70S6K (C) , ERK/MAPK (D) and PI3K/AKT (E)signaling. Supplementary Figure 7. Ectopic expression of miR-31 increases migration/invasion capabilities of H2228 cells. (A) Expression of miR-31 following infection with Lenti-miR vector containing miR-31 precursor was confirmed by TaqMan real-time PCR. (B) Cell invasion assay for miR-31 overexpressing H2228 cells. (C) Cell migration assay for miR-31 overexpressing H2228 cells using transwell membranes (upper panel, representative pictures of migration chambers; bottom panel, average counts from 10 random microscopic fields). The average counts were derived from ten random microscopic fields. (D) Cell proliferation assay for miR-31 overexpressing H2228 cells. Data are presented as mean plus-minus S.D. *P
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- 2023
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14. Supplementary Material and Methods from EpCAM-Regulated Transcription Exerts Influences on Nanomechanical Properties of Endometrial Cancer Cells That Promote Epithelial-to-Mesenchymal Transition
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Tim Hui-Ming Huang, Maria E. Gaczynska, Nameer B. Kirma, Victor X. Jin, Jianhua Ruan, Lu Liu, Yi-Wen Huang, Yao Wang, Pawel Osmulski, and Ya-Ting Hsu
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Transgenic mice,Immunofluorescence staining and image quantification, Proliferation and migration assays, ChIP-seq and network-based pathway analysis, TCGA expression analysis, CRISPR/Cas9 genome-editing of EpCAM, Apoptosis assay, Nanomechanical imaging of cells with Atomic Force Microscopy (AFM), Probing of cell surface with molecular recognition AFM
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- 2023
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15. Supplementary Table S5 from Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle–Related Transcription and Attenuated Androgen Response
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Tim H.-M. Huang, Chun-Liang Chen, Victor X. Jin, Qianben Wang, Wei-Ting Chao, Zhijie Liu, LuZhe Sun, Addanki P. Kumar, Michael A. Liss, Nameer B. Kirma, Chun-Lin Lin, Chiou-Miin Wang, Chia-Nung Hung, Rohit R. Jadhav, Anna D. Louie, Che-Kuang Lin, Yao Wang, and Aaron M. Horning
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Supplementary Table S5: Predictive values of the subcluser E gene panel for biochemical recurrence
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- 2023
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16. Supplementary Table S3 from Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle–Related Transcription and Attenuated Androgen Response
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Tim H.-M. Huang, Chun-Liang Chen, Victor X. Jin, Qianben Wang, Wei-Ting Chao, Zhijie Liu, LuZhe Sun, Addanki P. Kumar, Michael A. Liss, Nameer B. Kirma, Chun-Lin Lin, Chiou-Miin Wang, Chia-Nung Hung, Rohit R. Jadhav, Anna D. Louie, Che-Kuang Lin, Yao Wang, and Aaron M. Horning
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Supplementary Table S3: P values for significant differences between 0, 6, 12, 24, 36, and 72 hour R1881-treated LNCaP cells
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- 2023
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17. Supplementary Figure Legends from MicroRNA-31 Predicts the Presence of Lymph Node Metastases and Survival in Patients with Lung Adenocarcinoma
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Tim Lautenschlaeger, Victor X. Jin, Arnab Chakravarti, Carlo M. Croce, Patrick Ross, Leona W. Ayers, Sung-Suk Suh, Taewan Kim, Hiroshi Nakanishi, Stefano Volinia, Bin Li, Yao Wang, Alexander Huebner, Vaia Dedousi-Huebner, James Perry, Ri Cui, Zhenqing Ye, and Wei Meng
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PDF file, 64K.
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- 2023
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18. Supplementary Figures 1-10, Tables 1-3 from Targeted Methylation of Two Tumor Suppressor Genes Is Sufficient to Transform Mesenchymal Stem Cells into Cancer Stem/Initiating Cells
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Yu-Wei Leu, Shu-Huei Hsiao, Tim H.-M. Huang, Kenneth P. Nephew, Long-Bin Jeng, Kuen-daw Tsai, H. Sunny Sun, Chi-Sheng Wu, Yu-Sun Chang, Shaw-Jenq Tsai, Min-Jen Tseng, Victor X. Jin, Kun-Tu Yeh, Pei-Yi Chu, Kuan-Der Lee, Pei-Chi Hou, and I-Wen Teng
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Supplementary Figures 1-10, Tables 1-3 from Targeted Methylation of Two Tumor Suppressor Genes Is Sufficient to Transform Mesenchymal Stem Cells into Cancer Stem/Initiating Cells
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- 2023
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19. Supplementary Figure 1 from N-Myc Regulates a Widespread Euchromatic Program in the Human Genome Partially Independent of Its Role as a Classical Transcription Factor
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Paul S. Knoepfler, Peggy J. Farnham, Alice Wey, Jessica M. Lemen, Sheryl R. Krig, Victor X. Jin, and Rebecca Cotterman
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Supplementary Figure 1 from N-Myc Regulates a Widespread Euchromatic Program in the Human Genome Partially Independent of Its Role as a Classical Transcription Factor
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- 2023
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20. Supplementary Figures 1-6, Tables 1-15, Methods from Epigenetic Silencing Mediated through Activated PI3K/AKT Signaling in Breast Cancer
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Tim H.-M. Huang, Victor X. Jin, Alfred S. L. Cheng, Huey-Jen L. Lin, Charles L. Shapiro, Bhuvaneswari Ramaswamy, Cenny Taslim, Pei-Yin Hsu, Daniel E. Deatherage, Sandya Liyanarachchi, Yi-Wen Huang, Fei Gu, Rulong Shen, Yu-I Weng, Xun Lan, Ta-Ming Liu, and Tao Zuo
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Supplementary Figures 1-6, Tables 1-15, Methods from Epigenetic Silencing Mediated through Activated PI3K/AKT Signaling in Breast Cancer
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- 2023
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21. Data from Loss of Estrogen Receptor Signaling Triggers Epigenetic Silencing of Downstream Targets in Breast Cancer
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Tim H-M. Huang, Kenneth P. Nephew, Christoph Plass, Ramana V. Davuluri, Susan H. Wei, Wade V. Welshons, Edward M. Curran, Joseph C. Liu, Victor X. Jin, Meiyun Fan, Pearlly S. Yan, and Yu-Wei Leu
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Alterations in histones, chromatin-related proteins, and DNA methylation contribute to transcriptional silencing in cancer, but the sequence of these molecular events is not well understood. Here we demonstrate that on disruption of estrogen receptor (ER) α signaling by small interfering RNA, polycomb repressors and histone deacetylases are recruited to initiate stable repression of the progesterone receptor (PR) gene, a known ERα target, in breast cancer cells. The event is accompanied by acquired DNA methylation of the PR promoter, leaving a stable mark that can be inherited by cancer cell progeny. Reestablishing ERα signaling alone was not sufficient to reactivate the PR gene; reactivation of the PR gene also requires DNA demethylation. Methylation microarray analysis further showed that progressive DNA methylation occurs in multiple ERα targets in breast cancer genomes. The results imply, for the first time, the significance of epigenetic regulation on ERα target genes, providing new direction for research in this classical signaling pathway.
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- 2023
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22. Supplementary Table 1 from Loss of Estrogen Receptor Signaling Triggers Epigenetic Silencing of Downstream Targets in Breast Cancer
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Tim H-M. Huang, Kenneth P. Nephew, Christoph Plass, Ramana V. Davuluri, Susan H. Wei, Wade V. Welshons, Edward M. Curran, Joseph C. Liu, Victor X. Jin, Meiyun Fan, Pearlly S. Yan, and Yu-Wei Leu
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Supplementary Table 1 from Loss of Estrogen Receptor Signaling Triggers Epigenetic Silencing of Downstream Targets in Breast Cancer
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- 2023
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23. Data from N-Myc Regulates a Widespread Euchromatic Program in the Human Genome Partially Independent of Its Role as a Classical Transcription Factor
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Paul S. Knoepfler, Peggy J. Farnham, Alice Wey, Jessica M. Lemen, Sheryl R. Krig, Victor X. Jin, and Rebecca Cotterman
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Myc proteins have long been modeled to operate strictly as classic gene-specific transcription factors; however, we find that N-Myc has a robust role in the human genome in regulating global cellular euchromatin, including that of intergenic regions. Strikingly, 90% to 95% of the total genomic euchromatic marks histone H3 acetylated at lysine 9 and methylated at lysine 4 is N-Myc–dependent. However, Myc regulation of transcription, even of genes it directly binds and at which it is required for the maintenance of active chromatin, is generally weak. Thus, Myc has a much more potent ability to regulate large domains of euchromatin than to influence the transcription of individual genes. Overall, Myc regulation of chromatin in the human genome includes both specific genes, but also expansive genomic domains that invoke functions independent of a classic transcription factor. These findings support a new dual model for Myc chromatin function with important implications for the role of Myc in cancer and stem cell biology, including that of induced pluripotent stem cells. [Cancer Res 2008;68(23):9654–62]
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- 2023
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24. Adipokines Deregulate Cellular Communication via Epigenetic Repression of Gap Junction Loci in Obese Endometrial Cancer
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Srikanth R. Polusani, Chun Wei Chen, Guangcun Huang, Lu Liu, Nameer B. Kirma, Chiou Miin Wang, Sang Eun Lee, Ya Ting Hsu, Chun Liang Chen, Yufan Zhou, Nicholas D. Lucio, Philip T. Valente, Edward R. Kost, Jianhua Ruan, Maria Gaczynska, Tim H M Huang, David G. Mutch, Irene Aguilera-Barrantes, Eun Yong Shim, Chun-Lin Lin, Bruce J. Nicholson, Pawel A. Osmulski, Yi-Wen Huang, Pearlly S. Yan, Paul J. Goodfellow, Li Ling Lin, and Victor X. Jin
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0301 basic medicine ,Cancer Research ,Cell signaling ,Stromal cell ,Endometrial cancer ,Biology ,medicine.disease ,Transcriptome ,03 medical and health sciences ,030104 developmental biology ,Oncology ,Epigenetic Repression ,DNA methylation ,medicine ,Cancer research ,Stem cell ,Psychological repression - Abstract
Emerging evidence indicates that adipose stromal cells (ASC) are recruited to enhance cancer development. In this study, we examined the role these adipocyte progenitors play relating to intercellular communication in obesity-associated endometrial cancer. This is particularly relevant given that gap junctions have been implicated in tumor suppression. Examining the effects of ASCs on the transcriptome of endometrial epithelial cells (EEC) in an in vitro coculture system revealed transcriptional repression of GJA1 (encoding the gap junction protein Cx43) and other genes related to intercellular communication. This repression was recapitulated in an obesity mouse model of endometrial cancer. Furthermore, inhibition of plasminogen activator inhibitor 1 (PAI-1), which was the most abundant ASC adipokine, led to reversal of cellular distribution associated with the GJA1 repression profile, suggesting that PAI-1 may mediate actions of ASC on transcriptional regulation in EEC. In an endometrial cancer cohort (n = 141), DNA hypermethylation of GJA1 and related loci TJP2 and PRKCA was observed in primary endometrial endometrioid tumors and was associated with obesity. Pharmacologic reversal of DNA methylation enhanced gap-junction intercellular communication and cell–cell interactions in vitro. Restoring Cx43 expression in endometrial cancer cells reduced cellular migration; conversely, depletion of Cx43 increased cell migration in immortalized normal EEC. Our data suggest that persistent repression by ASC adipokines leads to promoter hypermethylation of GJA1 and related genes in the endometrium, triggering long-term silencing of these loci in endometrial tumors of obese patients. Significance: Studies reveal that adipose-derived stem cells in endometrial cancer pathogenesis influence epigenetic repression of gap junction loci, which suggests targeting of gap junction activity as a preventive strategy for obesity-associated endometrial cancer.
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- 2019
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25. Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle–Related Transcription and Attenuated Androgen Response
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Chun-Lin Lin, Michael A. Liss, Wei-Ting Chao, Yao Wang, Chiou Miin Wang, Rohit R. Jadhav, Chia Nung Hung, Addanki P. Kumar, Anna D Louie, Victor X. Jin, Chun Liang Chen, Lu-Zhe Sun, Aaron M. Horning, Che Kuang Lin, Nameer B. Kirma, Tim H M Huang, Qianben Wang, and Zhijie Liu
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Male ,0301 basic medicine ,Cancer Research ,medicine.drug_class ,Cell ,Biology ,Article ,03 medical and health sciences ,Prostate cancer ,Cell Line, Tumor ,LNCaP ,medicine ,Humans ,Mitosis ,Gene Expression Profiling ,CENPF ,Prostatic Neoplasms ,Cell cycle ,medicine.disease ,Androgen ,Androgen receptor ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Androgens ,Cancer research ,biology.protein ,RNA - Abstract
Increasing evidence suggests the presence of minor cell subpopulations in prostate cancer that are androgen independent and poised for selection as dominant clones after androgen deprivation therapy. In this study, we investigated this phenomenon by stratifying cell subpopulations based on transcriptome profiling of 144 single LNCaP prostate cancer cells treated or untreated with androgen after cell-cycle synchronization. Model-based clustering of 397 differentially expressed genes identified eight potential subpopulations of LNCaP cells, revealing a previously unappreciable level of cellular heterogeneity to androgen stimulation. One subpopulation displayed stem-like features with a slower cell doubling rate, increased sphere formation capability, and resistance to G2–M arrest induced by a mitosis inhibitor. Advanced growth of this subpopulation was associated with enhanced expression of 10 cell-cycle–related genes (CCNB2, DLGAP5, CENPF, CENPE, MKI67, PTTG1, CDC20, PLK1, HMMR, and CCNB1) and decreased dependence upon androgen receptor signaling. In silico analysis of RNA-seq data from The Cancer Genome Atlas further demonstrated that concordant upregulation of these genes was linked to recurrent prostate cancers. Analysis of receiver operating characteristic curves implicates aberrant expression of these genes and could be useful for early identification of tumors that subsequently develop biochemical recurrence. Moreover, this single-cell approach provides a better understanding of how prostate cancer cells respond heterogeneously to androgen deprivation therapies and reveals characteristics of subpopulations resistant to this treatment. Significance: Illustrating the challenge in treating cancers with targeted drugs, which by selecting for drug resistance can drive metastatic progression, this study characterized the plasticity and heterogeneity of prostate cancer cells with regard to androgen dependence, defining the character or minor subpopulations of androgen-independent cells that are poised for clonal selection after androgen-deprivation therapy. Cancer Res; 78(4); 853–64. ©2017 AACR.
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- 2018
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26. Abstract 3402: Castration resistance transcriptome in prostate cancer revealed by single-cell RNA-seq
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Tim H-M Huang, Chun Liang Chen, Michael A. Liss, Che-Kuang Lin, Brandon Lieberman, Jianhua Ruan, Ming Gao, Devalingam Mahalingam, Aaron M. Horning, Chiou-Miin Wang, Zhijie Liu, Yao Wang, Pei Wang, and Victor X. Jin
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Cancer Research ,ABL ,Wnt signaling pathway ,Biology ,medicine.disease ,Actin cytoskeleton ,Transcriptome ,Prostate cancer ,Circulating tumor cell ,Oncology ,Castration Resistance ,LNCaP ,Cancer research ,medicine - Abstract
Fatal metastatic castration-resistant prostate cancer (mCRPC) remains without sensitive early detection biomarkers and effective therapeutic targets. Among 2.5 millions of prostate cancer patients, the majority will face a dilemma, to treat or not to treat, at a point as cancer progresses. Biomarkers for mRCPC at an early stage represent an unmet need. With early identification, clinicians could design new treatment strategies to reduce metastasis-related morbidity and to extend survival of patients. In this study, we deployed single-cell RNA-seq on prostate cancer cells (LNCaP, ABL and PC3) to determine the transcriptome in androgen independency and castration resistance of prostate cancer. We identified potential 336 androgen-independence specific genes and 2396 castration resistance specific genes in ABL and PC3 cells respectively, while only 136 genes were shared in both cells. These genes, mostly upregulated were enriched in 43 and 166 signaling pathways that implicated the complexity of the castration resistance transcriptomic systems and networks. The signaling pathways are involved in advanced and metastatic malignancies including WNT, TGFB, ITGA/B, STAT, EPH, focal adhesion, adherens junction, regulation of actin cytoskeleton, gap junction, tight junction and EMT. Malignant potencies of ~ 40 pathways were validated by in silico analysis of the RNA-seq data from the prostate cancer cohort of The Cancer Genomic Atlas (TCGA) using Kaplan-Meier disease free and survival curve analyses. The transcriptomic regulation of these genes was further validated and correlated with ATAC-seq data. In order to further verify the functions of those signaling pathways in castration resistance, 9 major signaling pathways were evaluated using small molecule inhibitors. Castration resistant prostate cancer cells showed significant defective cell proliferation, migration, invasion and sphere formation in the presence of inhibitors, whereas LNCaP and ABL cells displayed limited or non-significant changes. Interestingly, 4 small molecule inhibitors showed significant suppression on the growth of stem-like circulating tumor cells that were derived from clinical blood samples of prostate cancer patients. Our data suggest that those castration resistance specific genes and signaling pathways revealed by single-cell RNA-seq may serve as potential markers and therapeutic targets. Citation Format: Aaron M. Horning, Che-Kuang Lin, Yao Wang, Brandon Lieberman, Devalingam Mahalingam, Ming Gao, Pei Wang, Chiou-Miin Wang, Zhijie Liu, Jianhua Ruan, Michael A. Liss, Victor X. Jin, Tim H-M Huang, Chun-Liang Chen. Castration resistance transcriptome in prostate cancer revealed by single-cell RNA-seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3402.
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- 2018
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27. Abstract 2990: Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis
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Xiaowen Zhang, Huai-Chin Chiang, Yao Wang, Chi Zhang, Victor X. Jin, Yanfen Hu, and Rong Li
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Cancer Research ,Oncology - Abstract
Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5′ end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development. Citation Format: Xiaowen Zhang, Huai-Chin Chiang, Yao Wang, Chi Zhang, Victor X. Jin, Yanfen Hu, Rong Li. Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2990.
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- 2018
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28. Abstract 5230: Modulation of SF3B1 causes global intron retention and downregulation of the B-cell receptor pathway in chronic lymphocytic leukemia
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Shuo Tu, Farrukh T. Awan, Jianbo Wang, Fang Shi, Qimei Han, Locke J. Bryan, Huidong Shi, Lirong Pei, Victor X. Jin, Austin Y. Shull, Thomas R. Webb, Libin Deng, Roni J. Bollag, Chandraiah Lagisetti, Eun Jeong Park, Jeong Hyeon Choi, and Hongbo Xin
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Cancer Research ,Venetoclax ,Chronic lymphocytic leukemia ,B-cell receptor ,breakpoint cluster region ,Biology ,medicine.disease ,Molecular biology ,chemistry.chemical_compound ,Oncology ,Downregulation and upregulation ,chemistry ,hemic and lymphatic diseases ,medicine ,Cancer research ,Idelalisib ,Protein kinase B ,PI3K/AKT/mTOR pathway - Abstract
Splicing factor SF3B1 is frequently mutated in chronic lymphocytic leukemia (CLL) patients and has been suggested as a potential therapeutic target. In this study, we demonstrated that SF3B1 modulator sudemycin D6 (SD6) effectively inhibits cell growth and induces apoptosis in CLL cells. RNA sequencing analysis revealed significant increases in global intron retention in SD6-treated CLL cells. Pathway analysis of the genes associated with increased intron retention suggested that B-cell receptor (BCR) and PI3K signaling pathways were among the most important pathways being affected by SD6. The increases in intron retention were inversely correlated with decreases in mRNA and protein levels of the affected BCR/PI3K pathway molecules including BLNK, BTK, AKT, PLCγ2, and PI3Kδ. SD6 treatment also induced a time-dependent exon-skipping event in MCL-1 mRNA and resulted in significant down-regulation of another anti-apoptotic gene TRAF1, thus collectively contributing to the SD6-induced apoptosis. Furthermore, SD6 treatment can overcome the pro-survival and pro-growth signals and synergize with established CLL therapies ibrutinib, idelalisib, and venetoclax to induce apoptosis in primary CLL cells co-cultured with bone marrow stromal cells and T-cell-derived cytokines. Finally, in vivo treatment with SD6 at 10mg/kg/day for 7 days significantly inhibited the growth of xenograft tumors that were established by subcutaneous inoculation of 5×106 MEC1 CLL cells into NOD mice. Collectively, these results provide a strong rationale for the future clinical development of spliceosome modulators and potential combination therapies for the treatment of CLL. Citation Format: Qimei Han, Jianbo Wang, Austin Y. Shull, Fang Shi, Libin Deng, Jeong-Hyeon Choi, Eun-Jeong Park, Shuo Tu, Lirong Pei, Farrukh T. Awan, Roni Bollag, Locke J. Bryan, Hong-bo Xin, Chandraiah Lagisetti, Thomas R. Webb, Victor Jin, Huidong Shi. Modulation of SF3B1 causes global intron retention and downregulation of the B-cell receptor pathway in chronic lymphocytic leukemia [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 5230.
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- 2019
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29. MicroRNA-31 Predicts the Presence of Lymph Node Metastases and Survival in Patients with Lung Adenocarcinoma
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Hiroshi Nakanishi, Stefano Volinia, Ri Cui, Arnab Chakravarti, Vaia Dedousi-Huebner, Sung Suk Suh, Wei Meng, Tim Lautenschlaeger, James Perry, Yao Wang, Taewan Kim, Bin Li, Zhenqing Ye, Carlo M. Croce, Patrick Ross, Alexander Huebner, Leona W. Ayers, and Victor X. Jin
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Cancer Research ,Pathology ,medicine.medical_specialty ,regulationgenetic ,studydisease ,studymaleprimary ,invasioncell ,journalRNA ,adultagedarticlecancer, prognosiscancer, stagingcancer, survivalcancer, tissuecell, invasioncell, migrationcell, proliferationcomputer, modelcontrolled, studydisease, markerfemalegene, expression, regulationgenetic, associationhumanhuman, cellhuman, tissuein, vitro, studylung, adenocarcinomalymph, node, metastasismajor, clinical, studymaleprimary, tumorpriority, journalRNA, sequencesignal, transductionsurvival, predictionupregulation ,modelcontrolled ,Biology ,node ,clinical ,NO ,markerfemalegene ,associationhumanhuman ,studylung ,predictionupregulation ,expression ,microRNA ,medicine ,adenocarcinomalymph ,transductionsurvival ,adultagedarticlecancer ,tissuecell ,Lymph node ,Cancer staging ,prognosiscancer ,tumorpriority ,Lung ,tissuein ,Proportional hazards model ,sequencesignal ,vitro ,medicine.disease ,stagingcancer ,migrationcell ,Gene expression profiling ,medicine.anatomical_structure ,metastasismajor ,Oncology ,survivalcancer ,proliferationcomputer ,Cohort ,Adenocarcinoma ,cellhuman - Abstract
Purpose: We conducted genome-wide miRNA-sequencing (miRNA-seq) in primary cancer tissue from patients of lung adenocarcinoma to identify markers for the presence of lymph node metastasis. Experimental Design: Markers for lymph node metastasis identified by sequencing were validated in a separate cohort using quantitative PCR. After additional validation in the The Cancer Genome Atlas (TCGA) dataset, functional characterization studies were conducted in vitro. Results: MiR-31 was upregulated in lung adenocarcinoma tissues from patients with lymph node metastases compared with those without lymph node metastases. We confirmed miR-31 to be upregulated in lymph node-positive patients in a separate patient cohort (P = 0.009, t test), and to be expressed at higher levels in adenocarcinoma tissue than in matched normal adjacent lung tissues (P < 0.0001, paired t test). MiR-31 was then validated as a marker for lymph node metastasis in an external validation cohort of 233 lung adenocarcinoma cases of the TCGA (P = 0.031, t test). In vitro functional assays showed that miR-31 increases cell migration, invasion, and proliferation in an ERK1/2 signaling-dependent manner. Notably, miR-31 was a significant predictor of survival in a multivariate cox regression model even when controlling for cancer staging. Exploratory in silico analysis showed that low expression of miR-31 is associated with excellent survival for T2N0 patients. Conclusions: We applied miRNA-seq to study microRNomes in lung adenocarcinoma tissue samples for the first time and potentially identified a miRNA predicting the presence of lymph node metastasis and survival outcomes in patients of lung adenocarcinoma. Clin Cancer Res; 19(19); 5423–33. ©2013 AACR.
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- 2013
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30. Epigenetic Silencing Mediated through Activated PI3K/AKT Signaling in Breast Cancer
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Daniel E. Deatherage, Xun Lan, Tao Zuo, Victor X. Jin, Ta-Ming Liu, Huey Jen L Lin, Rulong Shen, Charles L. Shapiro, Bhuvaneswari Ramaswamy, Cenny Taslim, Fei Gu, Pei Yin Hsu, Yi-Wen Huang, Sandya Liyanarachchi, Yu I. Weng, Alfred S. L. Cheng, and Tim H M Huang
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Cancer Research ,Epigenetic regulation of neurogenesis ,Gene Expression ,Breast Neoplasms ,Mice, SCID ,Biology ,medicine.disease_cause ,Article ,Histones ,Mice ,Phosphatidylinositol 3-Kinases ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Gene silencing ,Gene Silencing ,Epigenetics ,Cancer epigenetics ,PI3K/AKT/mTOR pathway ,Oligonucleotide Array Sequence Analysis ,Regulation of gene expression ,Reverse Transcriptase Polymerase Chain Reaction ,DNA Methylation ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Oncology ,DNA methylation ,Cancer research ,Female ,Carcinogenesis ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Trimethylation of histone 3 lysine 27 (H3K27me3) is a critical epigenetic mark for the maintenance of gene silencing. Additional accumulation of DNA methylation in target loci is thought to cooperatively support this epigenetic silencing during tumorigenesis. However, molecular mechanisms underlying the complex interplay between the two marks remain to be explored. Here we show that activation of PI3K/AKT signaling can be a trigger of this epigenetic processing at many downstream target genes. We also find that DNA methylation can be acquired at the same loci in cancer cells, thereby reinforcing permanent repression in those losing the H3K27me3 mark. Because of a link between PI3K/AKT signaling and epigenetic alterations, we conducted epigenetic therapies in conjunction with the signaling-targeted treatment. These combined treatments synergistically relieve gene silencing and suppress cancer cell growth in vitro and in xenografts. The new finding has important implications for improving targeted cancer therapies in the future. Cancer Res; 71(5); 1752–62. ©2011 AACR.
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- 2011
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31. Abstract 1800: Progesterone receptor attenuates STAT1-mediated interferon signaling in breast cancer
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Rashna Madan, Clive D'Santos, Zhao Lai, Tianbao Li, Qi Liu, Katherine R. Walter, Prabhakar Chalise, Jason S. Carroll, Gloria M. Trinca, Victor X. Jin, Christy R. Hagan, Merit L. Goodman, and Evangelia K. Papachristou
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Cancer Research ,biology ,business.industry ,Promoter ,medicine.disease ,Immune system ,Breast cancer ,Oncology ,Downregulation and upregulation ,Interferon ,Progesterone receptor ,medicine ,biology.protein ,Cancer research ,STAT1 ,business ,Transcription factor ,medicine.drug - Abstract
Why some tumors remain indolent and others progress to clinical relevance remains a major unanswered question in cancer biology. Interferon signaling in nascent tumors, mediated by STAT1, is a critical step through which the surveilling immune system can recognize and destroy developing tumors, thereby blocking their progression. We used an unbiased approach aimed at identifying nuclear protein interactions, called RIME, to identify novel progesterone receptor (PR) protein-protein interactions in T47D breast cancer cells. Using this technique, we identified a novel interaction between PR and STAT1. This interaction led to decreased interferon-induced STAT1 phosphorylation, a phenotype that was further potentiated in the presence of PR ligand. In human breast cancer samples, PR-positive tumors exhibited lower levels of phospho-STAT1 as compared to their PR-negative counterparts, indicating that this phenotype translates to human tumors. Breast cancer cells lacking PR expression exhibited higher levels of interferon-stimulated gene (ISG) RNA, the transcriptional endpoint of interferon activation, indicating that unliganded PR alone could decrease transcription of ISGs. Moreover, the absence of PR led to increased recruitment of STAT1, STAT2 and IRF9 (key transcription factors necessary for ISG transcription) to ISG promoters. These data indicate that PR, both in the presence and absence of ligand, attenuates interferon-induced STAT1 signaling, culminating in significantly abrogated activation of genes transcribed in response to interferons. PR-positive tumors may use downregulation of STAT1-mediated interferon signaling to escape immune surveillance, leading to the development of clinically relevant PR-positive tumors. Selective immune evasion of PR-positive tumors may be one explanation as to why over 70% of breast cancers are PR-positive at the time of diagnosis. Citation Format: Merit Goodman, Gloria Trinca, Katherine Walter, Evangelia Papachristou, Clive D'Santos, Tianbao Li, Qi Liu, Zhao Lai, Prabhakar Chalise, Rashna Madan, Victor Jin, Jason Carroll, Christy Hagan. Progesterone receptor attenuates STAT1-mediated interferon signaling in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1800.
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- 2018
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32. Abstract P6-05-03: Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis
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Yao Wang, Yanfen Hu, Huai-Chin Chiang, Xiaowen Zhang, Chi Zhang, Victor X. Jin, and Rong Li
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Cancer Research ,Oncology ,biology ,R-loop ,Chemistry ,Attenuation ,biology.protein ,medicine ,RNA polymerase II ,Carcinogenesis ,medicine.disease_cause ,Cell biology - Abstract
Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5' end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development. Citation Format: Zhang X, Chiang H-C, Wang Y, Jin VX, Hu Y, Li R. Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-05-03.
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- 2018
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33. Abstract P6-07-02: Amplified DERE-mediated epigenetic repression in ERα-mediated breast tumorigenesis
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Victor X. Jin, Pei-Yin Hsu, Tim H-M Huang, Hang-Kai Hsu, Yi Chen, and Zelton D Sharp
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Genetics ,Cancer Research ,Biology ,medicine.disease_cause ,Chromatin ,Cell biology ,Oncology ,Epigenetic Repression ,DNA methylation ,Transcriptional regulation ,medicine ,H3K4me3 ,Heterochromatin protein 1 ,Epigenetics ,Carcinogenesis - Abstract
Epidemiological studies reveal that maternal exposure to estrogenic chemicals during pregnancy results in higher risk of breast cancer in offspring. One of possible causal mechanisms is epigenetic reprogramming, but how estrogen/ERα signaling contributes to tumorigenesis through epigenetic machinery remains unclear. In this study, we demonstrate that the epigenetic modulation mediated by estrogen-driven amplification of distant-acting regulatory elements, or enhancers, may be an explanation addressing to this question. Enhancers contain transcription factor binding sites known to remotely regulate transcription through chromatin looping or transvection. Using our in vitro model to mimic maternal estrogen exposure and a "Seq-to-Seek" strategy integrating three next-generation sequencing approaches, we comprehensively mapped distant estrogen response elements (DEREs) that remotely control transcription of target genes through chromatin proximity. Surprisingly, a densely mapped DERE region located on chromosome 20q13 frequently amplifies in ERα-positive breast cancer with poor prognosis. Progressive accumulation of DERE copies was observed in normal breast progenitor and cancer cells chronically exposed to estrogen. Upon estrogen stimulation, these aberrantly amplified DEREs are clustered as a potential transcriptional depot for suppressing target gene expression through altering chromatin interactions, leading to accumulation of repressive histone marks (e.g. trimethylated H3K27 and H3K9), polycomb repressive complex 2, the presence of heterochromatin protein 1 (HP1) and DNA methylation, following prevention of RNA polymerase II and active histone mark- H3K4me3 binding. Furthermore, neutralization of HP1 function can significantly attenuate estrogen-driven DERE clustering and DERE-mediated repressive chromatin interactions, resulting in inhibition of cell proliferation. Deletion of the interested DERE regions using CRISPR/Cas9 genomic editing system further demonstrated that DERE-driven remote transcriptional control play a crucial role in tumor cell growth. Our data support a model in which amplified DEREs preferentially induce repressive epigenetic modulation of target genes. These findings indicate that 20q13 DERE region is a potential transcriptionally repressive domain whose aberrant amplification can result in suppressing expression of tumor suppressor genes, leading to tumorigenesis. In summary, our findings suggest that amplification of DNA regulatory elements can profoundly alter target transcriptome during tumorigenesis and amplified DEREs can be used as potential prognostic markers for endocrine resistance and predicative for progeny at risk of breast cancer. Citation Format: Pei-Yin Hsu, Hang-Kai Hsu, Yi-dong Chen, Victor X Jin, Zelton D Sharp, Tim H-M Huang. Amplified DERE-mediated epigenetic repression in ERα-mediated breast tumorigenesis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-07-02.
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- 2015
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34. Abstract 2874: Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development
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Victor X. Jin, Yanfen Hu, Rong Li, Jianhua Ruan, Sreejith J. Nair, Xiaowen Zhang, Jamiul Jahid, Huai-Chin Chiang, and Yao Wang
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Genetics ,Cancer Research ,DNA repair ,Morphogenesis ,Regulator ,Biology ,Cell biology ,chemistry.chemical_compound ,Oncology ,chemistry ,Transcription (biology) ,Transcriptional regulation ,Antagonism ,Homologous recombination ,DNA - Abstract
Breast cancer susceptibility gene BRCA1 is well known for its function in double strand break (DSB) DNA repair. While BRCA1 is also implicated in transcriptional regulation, the physiological significance remains unclear. Cofactor of BRCA1 (COBRA1) is a BRCA1-binding protein and an important regulator of transcription elongation. Here we used mouse genetics to interrogate functional interaction between BRCA1 and COBRA1 during mammary gland development. Tissue-specific deletion of Cobra1 reduced mammary epithelial compartments and blocked ductal morphogenesis, alveologenesis, and lactogenesis, demonstrating a pivotal role of COBRA1 in adult tissue development. Remarkably, these developmental deficiencies due to Cobra1 knockout were largely rescued by additional loss of full-length Brca1. Furthermore, Brca1/Cobra1 double knockout restored developmental transcription at puberty, altered luminal epithelial homeostasis, yet remained deficient in homologous recombination-based DSB repair. Thus our genetic suppression analysis uncovers a previously unappreciated, DNA repair-independent function of BRCA1 in antagonizing COBRA1-dependent transcription program during mammary gland development. Citation Format: Xiaowen Zhang, Sreejith J. Nair, Huai-Chin Chiang, Yao Wang, Md Jamiul Jahid, Jianhua Ruan, Victor X. Jin, Yanfen Hu, Rong Li. Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development. [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 2874.
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- 2016
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35. Abstract 4607: Mediator kinase module as a transducer of oncogenic Wnt/beta-catenin signaling
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Fangjian Gao, Marieke Oldenbroek, Alison D. Clark, Victor X. Jin, Yao Wang, Thomas G. Boyer, and Jason M. Spaeth
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Cancer Research ,Mediator ,Oncology ,Kinase ,Cancer research ,Wnt signaling pathway ,Cyclin-dependent kinase 8 ,Kinase activity ,Biology ,Transcription factor ,Cyclin ,MED12 - Abstract
Dysregulation of Wnt/β-catenin signaling promotes colorectal cancer (CRC) and other types of malignancies through unprogrammed changes in gene transcription that drive tumorigenesis. CDK8 is a CRC oncoprotein whose amplification-dependent overexpression identifies a significant subset of CRC patients with poor prognosis. CDK8 kinase activity, along with Cyclin C (CycC), drives tumorigenesis by stimulating β-catenin transcriptional activity. Thus, inhibition of CDK8 kinase function offers a promising therapeutic approach for CDK8-overexpressing CRCs. CycC-CDK8, along with MED12 and MED13, compose a four-subunit “kinase” module within Mediator, a conserved multiprotein interface between gene-specific transcription factors and RNA Polymerase II. We have previously identified a network of physical and functional interactions within the Mediator kinase module critical for oncogenic Wnt/β-catenin signaling. Mechanistically, β-catenin binds directly to MED12 in Mediator, thus activating CycC-dependent CDK8 kinase activity and β-catenin transcriptional activity. More specifically, MED12-dependent CDK8 activation occurs through a direct interaction involving the MED12 N-terminus and a phylogenetically conserved surface groove on CycC. Here, we demonstrate that mutagenic disruption of the MED12/CycC interface in CRC cell lines leads to uncoupling of CycC-CDK8 to MED12 and core Mediator, and concomitant loss of Mediator-associated CDK8 activity. Transcriptome analysis of cells lacking CDK8 kinase function revealed downregulation of Wnt/β-catenin signaling and other oncogenic pathways, consequently impairing CRC cell proliferation and clonogenicity. Our studies therefore identify the MED12/CycC interface as a critical transducer of oncogenic Wnt/β-catenin signaling. By validating MED12/CycC as a potential therapeutic target, our findings have significant implications in current methods of treating CRC as they pave a way for development of novel, targeted inhibitors of Wnt/β-catenin signaling to treat colorectal and other CDK8-driven driven malignancies. Supported by MH085320-05 (TGB), RP140435 (TGB) and T32DE14318 (ADC). Citation Format: Alison Clark, Marieke Oldenbroek, Yao Wang, Jason Spaeth, Fangjian Gao, Victor X. Jin, Thomas Boyer. Mediator kinase module as a transducer of oncogenic Wnt/beta-catenin signaling. [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 4607.
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- 2016
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36. Abstract 2871: Dual role of EpCAM cleavage in adhesion attenuation and transcription enhancement for cell migration
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Victor X. Jin, Tim H M Huang, Ya-Ting Hsu, Yao Wang, Lu Liu, Nameer B. Kirma, Jianhua Ruan, Yi-Wen Huang, Maria Gaczynska, and Pawel A. Osmulski
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Cancer Research ,Dual role ,Oncology ,Chemistry ,Transcription (biology) ,Cell migration ,Cleavage (embryo) ,Molecular biology ,Cell biology - Abstract
Epithelial cell adhesion molecule (EpCAM), a membrane protein known to modulate cell-cell adhesion, is also a regulatory molecule internalized into the nucleus for transcriptional control of gene expression. Here we demonstrate that activated EGF/EGFR is a signaling factor to drive the cleavage of the extracellular fragment EpEX culminating in removal of cell-surface EpCAM as monitored with recognition atomic force microscopy (AFM). As a result, internalization of the cytoplasmic domain EpICD leads to formation of transcription factor complexes with LEF1 that regulate gene transcription for enhancing mobility functions of cancer cells. Comprehensive probing with AFM further reveals increased elasticity and decreased adhesiveness of these cells, implicating acquisition of an epithelial-mesenchymal transition phenotype. While EpCAM cleavage contributes to the loss of cell-surface adhesiveness, its internalized EpICD additionally regulates targets for promoting cell migration. Thus, this EGF/EGFR-modulated action on structural EpCAM and regulatory EpICD can enhance invasion potential of transformed cells. Citation Format: Ya-Ting Hsu, Pawel A. Osmulski, Yao Wang, Yi-Wen Huang, Lu Liu, Jianhua Ruan, Victor X. Jin, Nameer B. Kirma, Maria E. Gaczynska, Tim H.M. Huang. Dual role of EpCAM cleavage in adhesion attenuation and transcription enhancement for cell migration. [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 2871.
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- 2016
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37. Loss of Estrogen Receptor Signaling Triggers Epigenetic Silencing of Downstream Targets in Breast Cancer
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Yu-Wei Leu, Wade V. Welshons, Pearlly S. Yan, Edward M. Curran, Ramana V. Davuluri, Tim H M Huang, Meiyun Fan, Joseph Liu, Christoph Plass, Susan H. Wei, Victor X. Jin, and Kenneth P. Nephew
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Cancer Research ,Base Sequence ,Reverse Transcriptase Polymerase Chain Reaction ,Estrogen receptor ,Breast Neoplasms ,Methylation ,Biology ,Epigenesis, Genetic ,DNA demethylation ,Histone ,Receptors, Estrogen ,Oncology ,Cell Line, Tumor ,DNA methylation ,Cancer research ,biology.protein ,Humans ,Gene silencing ,RNA Interference ,Gene Silencing ,Epigenetics ,Cancer epigenetics ,Receptors, Progesterone ,DNA Primers ,Signal Transduction - Abstract
Alterations in histones, chromatin-related proteins, and DNA methylation contribute to transcriptional silencing in cancer, but the sequence of these molecular events is not well understood. Here we demonstrate that on disruption of estrogen receptor (ER) α signaling by small interfering RNA, polycomb repressors and histone deacetylases are recruited to initiate stable repression of the progesterone receptor (PR) gene, a known ERα target, in breast cancer cells. The event is accompanied by acquired DNA methylation of the PR promoter, leaving a stable mark that can be inherited by cancer cell progeny. Reestablishing ERα signaling alone was not sufficient to reactivate the PR gene; reactivation of the PR gene also requires DNA demethylation. Methylation microarray analysis further showed that progressive DNA methylation occurs in multiple ERα targets in breast cancer genomes. The results imply, for the first time, the significance of epigenetic regulation on ERα target genes, providing new direction for research in this classical signaling pathway.
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- 2004
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38. EGFR-Dependent Regulated Intramembrane Proteolysis of EpCAM—Response
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Victor X. Jin, Tim H M Huang, Yao Wang, Yi-Wen Huang, Pawel A. Osmulski, Nameer B. Kirma, Lu Liu, Jianhua Ruan, Maria Gaczynska, and Ya Ting Hsu
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0301 basic medicine ,Cancer Research ,Proteolysis ,Cell ,Regulated Intramembrane Proteolysis ,Cell membrane ,03 medical and health sciences ,ErbB Receptors ,chemistry.chemical_compound ,Antigens, Neoplasm ,medicine ,Humans ,Neoplasm ,medicine.diagnostic_test ,Endometrial cancer ,Cell Membrane ,Epithelial cell adhesion molecule ,Epithelial Cell Adhesion Molecule ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,Cancer research - Abstract
We would like to thank Dr. Gires for the letter concerning our article ([1][1]). We are very glad that Dr. Gires considers our data on how EGFR activation affects endometrial cancer cell invasiveness via EpCAM activity novel and interesting. The study highlights not only the function of EpCAM as a
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- 2017
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39. Abstract 4778: HP1-mediated spatiotemporal control of estrogen-responsive transcription in breast cancer cells
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Victor X. Jin, Tim H M Huang, Pei-Yin Hsu, Zelton D Sharp, and Hang-Kai Hsu
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Oncology ,Cancer Research ,medicine.medical_specialty ,Estrogen ,medicine.drug_class ,Transcription (biology) ,Internal medicine ,medicine ,Cancer research ,Heterochromatin protein 1 ,Breast cancer cells ,Biology - Abstract
Recruitment of transcriptional machinery to target promoters for aberrant gene expression has been well studied, but underlying control directed by distant-acting enhancers remains unclear in cancer development. Our previous study demonstrated that distant estrogen response elements (DEREs) located on chromosome 20q13 were frequently amplified (50∼60 copies) and translocated to other chromosomes in ERα-positive breast cancer cells. In this study, we used three-dimensional interphase fluorescence in situ hybridization to decipher spatiotemporal gathering of multiple DEREs in the nucleus. Upon estrogen stimulation, the majority of 20q13 DEREs were mobilized to form regulatory depots for synchronized regulation of target loci. A chromosome conformation capture assay coupled with chromatin immunoprecipitation further uncovered that ERα-bound regulatory depots are tethered to heterochromatin protein 1 (HP1) for coordinated chromatin movement and subsequent facilitation of histone modifications of target loci, resulting in transcription repression. Neutralizing HP1 function dissembled these regulatory depots and reversed this transcription inactivation of candidate tumor-suppressor genes. Deletion of amplified DEREs using the CRISPR/Cas9 genomic-editing system profoundly altered transcriptional profiles of JAK/STAT signaling networks, leading to proliferation inhibition of cancer cells with beneficial outcome of breast cancers. These findings reveal a formerly uncharacterized feature of oncogenic amplicons that multiple copies of the amplicon congregate as transcriptional unions in the nucleus for synchronous regulation of function-related loci in tumorigenesis. Disruption of their assembly can be a new strategy for treating breast cancers and other malignancies. Citation Format: Pei-Yin Hsu, Hang-Kai Hsu, Victor X. Jin, Zelton D. Sharp, Tim H.-M. Huang. HP1-mediated spatiotemporal control of estrogen-responsive transcription in breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4778. doi:10.1158/1538-7445.AM2015-4778
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- 2015
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40. Abstract 4783: Amplification of distant estrogen response elements epigenetically deregulates target genes in ERα-mediated breast tumorigenesis
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Tim H M Huang, Pei-Yin Hsu, Victor X. Jin, Hang-Kai Hsu, and Zelton D Sharp
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Genetics ,Cancer Research ,Biology ,Amplicon ,medicine.disease_cause ,Chromatin ,DNA binding site ,Histone ,Oncology ,medicine ,biology.protein ,Cancer research ,Epigenetics ,Carcinogenesis ,Enhancer ,Gene - Abstract
Since the first amplified gene, MYCN, was identified in neuroblastomas, considerable effort has been directed toward discovery of oncogenes in amplified genomic regions. However, there is no significant correlation between copy number gains and increased expression of corresponding genes within amplicons. We demonstrate that amplification of distant-acting regulatory elements, or enhancers, may be an alternative mechanism contributing to an oncogenic event. Enhancers comprise transcription factor binding sites known to remotely regulate transcription through chromatin looping or transvection. Using a “Seq-to-Seek” strategy integrating three next-generation sequencing approaches, we comprehensively mapped distant estrogen response elements (DEREs) that remotely control transcription of target genes through chromatin proximity. Surprisingly, a densely mapped DERE region located on chromosome 20q13 frequently amplifies in ERα-positive breast cancer with poor prognosis. Progressive accumulation of DERE copies was observed in normal breast progenitor and cancer cells chronically exposed to estrogen or estrogenic chemicals. Pharmacological studies with either an ERα antagonist or an ataxia telangiectasia mutated (ATM) kinase inhibitor further showed that ATM-dependent DNA repair pathway participates in ERα-driven increase of 20q13 DERE copies, suggesting involvement of breakage-fusion-bridge mechanism in DERE amplification. Furthermore, these aberrantly amplified DEREs altered chromatin interactions, leading to transcriptional repression of genes that are associated with tumor-suppressor and apoptosis pathways and potentially linked to cancer development and tamoxifen resistance. Correlation analyses of copy-number variation, occupancy of the repressive histone mark, H3K27me3, and methylation profiling of 20q13 DEREs in ERα-positive cancer cells support a model in which amplified DEREs preferentially induce repressive epigenetic modulation of target genes. In addition, interphase fluorescence in situ hybridization coupled with immunofluorescence analyses revealed that estrogen stimulation leads to DERE clustering in a transcriptional hub nearby in a heterochromatic region. These findings indicate that the 20q13 DERE region is a potential transcriptionally repressive domain whose aberrant amplification can result in suppressing expression of tumor suppressor genes. To determine the precise role of amplified DEREs in epigenetic transcription and their biological significance, our ongoing studies use CRISPR/Cas genomic editing system to delete candidate DEREs at 20q13. In summary, our findings suggest that amplification of DNA regulatory elements can profoundly alter target transcriptome during tumorigenesis and amplified DEREs can be used as potential prognostic markers for endocrine resistance. Citation Format: PEI-YIN HSU, HANG-KAI HSU, Victor X. Jin, Zelton D. Sharp, Tim H.-M. Huang. Amplification of distant estrogen response elements epigenetically deregulates target genes in ERα-mediated breast tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4783. doi:10.1158/1538-7445.AM2014-4783
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- 2014
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41. Abstract 1376: EpCAM-mediated hypomethylation of BMP and cell adhesion genes is associated with advanced endometrial cancer
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Jianhua Ruan, Fei Gu, Ya-Ting Hsu, Hung Cheng Lai, Victor X. Jin, Chun Liang Chen, Yi-Wen Huang, Paul J. Goodfellow, Rohit R. Jadhav, Tim H M Huang, Rui Lan Huang, Chiou-Miin Wang, Joseph Liu, Ian M. Thompson, Nameer B. Kirma, Yao Wang, and David G. Mutch
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Cancer Research ,Oncogene ,biology ,Endometrial cancer ,Epithelial cell adhesion molecule ,Bioinformatics ,medicine.disease ,Metastasis ,chemistry.chemical_compound ,Histone ,Oncology ,chemistry ,DNA methylation ,Cancer research ,biology.protein ,medicine ,Epidermal growth factor receptor ,Epigenetics - Abstract
Endometrial cancer (EC) is the most common gynecologic malignancy, with approximately 20% of EC patients developing advanced stage recurrent tumors and frequent metastasis. Our goal was to investigate whether DNA methylation signatures associated with low promoter methylation (hypomethylation) and specific oncogenic signaling delineate predictive markers of endometrial cancer recurrence. Global screening by Methyl-CpG-capture sequencing revealed aberrant DNA methylation in our endometrial cancer cohort and identified a subset of bone morphogenetic protein family (BMP1, 2, 3, 4, and 7) exhibiting frequent hypomethylation in primary tumors with subsequent recurrence compared with non-recurrent tumors. This epigenetic signature correlated with poor survival and was validated in The Cancer Genome Atlas endometrial cancer cohort. Our functional studies also implicated epidermal growth factor receptor (EGFR) pathway in the transcriptional activation of these BMPs and inducing epithelial-mesenchymal transition (EMT). In addition to AKT and MAPK, the epithelial cell adhesion molecule (EpCAM) mediated these actions by EGFR. EpCAM involvement in cancer progression includes nuclear co-translocation of its intracellular domain EpICD with Lef-1 complexes and targeting oncogene promoter activation. In this study, EGF stimulated EpICD-Lef-1 binding on BMP genes accompanied with histone active modification marks. EpICD knockdown resulted in increased repressive histone marks and DNA methylation at these loci, suggesting that EpICD occupancy is involved in their epigenetic modification to an open transcriptional conformation. Knockdown of candidate BMPs led to decreased endometrial cancer cell invasiveness, implicating them in aggressive growth. Extending our studies, we performed ChIP-Seq analysis to identify global regulation by the EpICD-Lef-1 complexes in endometrial cancer. Interestingly, under basal levels only about 28% of loci targeted by either EpICD or Lef-1 were commonly targeted by EpICD-Lef-1, with common targets increasing to about 50% in 24 hrs and 73% in 48 hrs post EGF treatment. This indicates that EGFR signaling stimulates a time-course dependent enrichment of EpICD-Lef-1 convergence on target loci. Our initial studies of these EpICD target pathways included genes with cell adhesion functions. Future studies on the regulation of the EpICD-Lef-1 regulated genes and their mechanisms of action in aggressive endometrial cancer will provide a better understanding of this gene network in endometrial cancer. Hypomethylation signatures of candidate loci in this regulatory network may present putative predictive markers of poor survival and which may be used to tailor individualized therapy. Citation Format: Ya-Ting Hsu, Fei Gu, Yi-Wen Huang, Joseph Liu, Jianhua Ruan, Rui-Lan Huang, Chiou-Miin Wang, Chun-Liang Chen, Rohit R. Jadhav, Yao Wang, Victor X. Jin, Hung-Cheng Lai, David G. Mutch, Paul J. Goodfellow, Ian M. Thompson, Nameer B. Kirma, Tim H.M. Huang. EpCAM-mediated hypomethylation of BMP and cell adhesion genes is associated with advanced endometrial cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1376. doi:10.1158/1538-7445.AM2014-1376
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- 2014
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42. Abstract 3341: Cross-talk between PI3K/AKT and ERα signaling leads to STAT3/6-modulated epigenetic transcription in aggressive breast cancer
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Yao Wang, Pei-Yin Hsu, Hang-Kai Hsu, Victor X. Jin, Zelton D Sharp, and Tim H M Huang
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Cancer Research ,Biology ,medicine.disease_cause ,Bioinformatics ,chemistry.chemical_compound ,Oncology ,chemistry ,Tumor progression ,STAT protein ,medicine ,Cancer research ,biology.protein ,LY294002 ,Carcinogenesis ,STAT3 ,Protein kinase B ,Transcription factor ,PI3K/AKT/mTOR pathway - Abstract
The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is a critical survival cascade in tumor progression. Our previous study demonstrated that combinational treatment of a potent PI3K inhibitor, LY294002 (LY), and DNA methyltransferase inhibitor, 5’-Aza-deoxycytidine (DAC), compounds effectively reduce tumor formation in the immunodeficiency mouse model, suggesting that PI3K/AKT signaling suppresses tumorigenesis through the epigenetic modulation. While tumor size of the LY-treated xenografts is dramatically decreased compared to the control group, the tumor growth cannot be completely attenuated by either LY or LY/DAC treatment, indicating that there is an alternative route for tumor survival. Here, we performed a microarray analysis to identify LY-mediated expression profiling on an ERα-positive breast cancer cell line, T-47D, the cell line applied in the previous xenograft experiments. A subset of 24 LY-activated genes associated with better clinical outcome are found to be not only direct targets of PI3K/AKT but involved in estrogen (E2)/ERα signaling by ingenuity pathway analysis, suggesting the involvement of ERα signaling in PI3K/AKT-mediated tumor growth. To clarify their relationship, pharmacological experiments using an ERα antagonist, ICI 182, 780 (ICI) and LY coupled with E2 was conducted. We observed that E2 stimulation induces both AKT and ERα activation in a time-dependent manner. Either ICI or LY treatment cannot repress the activation levels of AKT or ERα, respectively. Though, either single or combined inhibitor treatment can effectively restore E2-suppressed gene expression. These findings indicate that cross-talk between PI3K/AKT and ERα signaling cascades may cooperatively regulate cell growth and associated gene expression. In addition, transcription factor motif analysis showed that signal transducer and activator of transcription 3 and 6 (STAT3/6) binding motifs are enriched with highest prediction score on the promoter regions of the examined AKT-directed targets. Inhibitors prohibit E2-mediated assembly of STAT3/6 with ERα and STAT3/6 recruitment onto the promoter regions of target loci using co-immunoprecipitation (co-IP) and chromatin IP-qPCR. Moreover, repressive histone marks, H3K27me3 and H3K9me3, are found to occupy on the same regions as STAT3/6 upon E2 treatment. DAC treatment can effectively restore E2-induced suppression of AKT-directed target genes. Further association studies are ongoing to interrogate whether STAT3/6 is part of repressive transcription complex with H3K27me3 and H3K9me3. In summary, we propose that cross-talk of ERα with PI3K/AKT signaling represents the potential function switch of ERα from genomic binding to no-genomic binding. Combined treatment of PI3K/AKT inhibitors with hormone therapy may shed a light of therapeutic strategy to patients with aggressive or metastatic breast tumors. Citation Format: Hang-Kai Hsu, Pei-Yin Hsu, Yao Wang, Zelton D. Sharp, Tim H.-M. Huang, Victor X. Jin. Cross-talk between PI3K/AKT and ERα signaling leads to STAT3/6-modulated epigenetic transcription in aggressive breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3341. doi:10.1158/1538-7445.AM2014-3341
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- 2014
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43. Abstract A21: Direct transcriptional functions of the APC tumor suppressor in regulating gene expression
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Anil G. Jegga, Xun Lan, Victor X. Jin, William Hankey, Michael A. McIlhatton, Bruce J. Aronow, and Joanna Groden
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Genetics ,Cancer Research ,Candidate gene ,Tumor suppressor gene ,Chromatin binding ,Tumor initiation ,Biology ,medicine.disease_cause ,Oncology ,Tumor progression ,Gene expression ,medicine ,Cancer research ,Carcinogenesis ,Gene - Abstract
Mutation of the APC tumor suppressor gene occurs in approximately 75% of colorectal cancers (CRC) and is considered the central event driving tumor initiation in the large intestine. The APC protein controls gene expression indirectly through the canonical WNT signaling pathway as a component of a cytoplasmic complex that promotes the proteolysis of the transcriptional co-regulator β-catenin. Recent studies have shown that APC is also a chromatin-associated protein that interacts with the promoter of the MYC proto-oncogene to downregulate its transcription. We have tested the hypothesis that APC similarly regulates other genes relevant to tumorigenesis, and that the 75% of CRCs that are deficient in APC may show abnormal activation or suppression of these genes, in comparison to the other 25% of CRCs. These differences could potentially underlie differences in tumor progression and/or responses to chemotherapy, and could enable the identification of new therapeutic targets. The APC genotype of two CRC cell lines was manipulated using siRNA to reduce APC expression in one cell line wild-type for APC and using an APC transgene to induce exogenous APC expression in a second cell line mutated for APC. NanoString and RNA-seq technologies have generated gene expression datasets from these cell lines and identify more than 700 genes that could be directly regulated at the transcriptional level by APC. RT-PCR and in silico analyses have validated a smaller subset of these genes. Functional pathway analysis has led to the hypothesis that APC loss facilitates evasion of apoptosis, with a subset of 17 pro- and anti-apoptotic candidate genes implicated in this effect. Critical experiments in progress will confirm the extent to which the aberrant expression of these genes in vivo is specific to colon tumors lacking APC, using Apc-deficient and Apc-wild-type mouse models of intestinal cancer, and will identify direct chromatin binding sites of APC by ChIP-seq. These approaches will validate our gene expression analyses and identify a set of direct gene targets that APC regulates. Citation Format: William Hankey, Michael A. McIlhatton, Xun Lan, Anil G. Jegga, Victor X. Jin, Bruce J. Aronow, Joanna Groden. Direct transcriptional functions of the APC tumor suppressor in regulating gene expression. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A21.
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- 2013
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44. Abstract 2963: 5-hydroxymethylcytosine alterations at H3K9me3 marked genomic regions serve as potential biomarker for renal cell carcinoma patients
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Pearlly S. Yan, Zhenqing Ye, David Frankhouser, Victor X. Jin, Wei Meng, Arnab Chakravarti, Tim Lautenschlaeger, and Alexander Huebner
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Cancer Research ,Pathology ,medicine.medical_specialty ,Kidney ,Cancer ,Urine ,Biology ,urologic and male genital diseases ,medicine.disease_cause ,medicine.disease ,Malignancy ,medicine.anatomical_structure ,Oncology ,Renal cell carcinoma ,DNA methylation ,medicine ,Epigenetics ,Carcinogenesis - Abstract
Background: Epigenetic alterations are frequently encountered in many malignancies. Control of DNA methylation is thought to play a critical role in the global epigenetic reprogramming observed during development and carcinogenesis. DNA demethylation is initiated by the transition from 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). While 5mC patterns are relatively well characterized in many malignancies, not much is known about 5hmC patterns and the potential usefulness as biomarkers. We thus sought out to identify 5hmC alterations in renal cell carcinoma (RCC) and assess their potential usefulness as urine biomarkers. Results: We performed genome-wide 5hmC MethylCap-seq on one pooled RCC tissue sample (n = 3) and the corresponding pooled matched normal kidney tissue (n = 3), as well as on one pooled urine sample obtained from RCC patients (n = 52) and one pooled urine sample obtained from control patients without malignancy (n = 65). Global 5hmC levels were dramatically reduced in RCC tissues compared to matched normal adjacent kidney tissues, and in urine samples compared to tissue samples. Assessing histone marked regions we found 5hmC levels to be highly enriched in H3K9me3 marked repressive genomic regions of RCC tissue compared to normal adjacent tissues. Given the low 5hmC signal in these regions in normal tissues, this difference was also clearly identified comparing urine samples from RCC patients to control patients without RCC. Conclusions: We characterized the 5hmC distribution of RCC and normal human renal tissue as well as of urine samples from RCC patients and control patients without RCC. We identified dramatic genome-wide 5hmC changes to occur during carcinogenesis, which have potential for development as non-invasive urine biomarkers. Citation Format: Wei Meng, Tim Lautenschlaeger, David Frankhouser, Zhenqing Ye, Alexander Huebner, Victor Jin, Pearlly Yan, Arnab Chakravarti. 5-hydroxymethylcytosine alterations at H3K9me3 marked genomic regions serve as potential biomarker for renal cell carcinoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2963. doi:10.1158/1538-7445.AM2015-2963
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- 2015
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45. Abstract 1009: Regression of rectal polyps in familial adenomatous polyposis patients by freeze-dried black raspberries is associated with the demethylation and reactivation of tumor suppressor genes
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Victor X. Jin, Tim H M Huang, Henrietta Hasson, Chieh-Ti Kuo, Fei Gu, Carol A. Burke, Yi-Wen Huang, Li-Shu Wang, Claire Seguin, Christine Sardo, Kristen Stoner, and Gary D. Stoner
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Cancer Research ,Pathology ,medicine.medical_specialty ,biology ,business.industry ,Rectum ,Cancer ,Suppository ,biology.organism_classification ,medicine.disease ,Gastroenterology ,Familial adenomatous polyposis ,medicine.anatomical_structure ,Oncology ,Black raspberry ,CDKN2A ,Internal medicine ,medicine ,Rectal Polyp ,business ,Aberrant crypt foci - Abstract
We previously reported in a Phase I clinical trial that black raspberry (BRB) powder is well tolerated by humans when administered in a slurry of water at 45g/day for 7 days. We then undertook a study to determine if BRB might regress rectal polyps in familial adenomatous polyposis (FAP) patients. Fourteen FAP patients who had undergone a colectomy were treated with BRB daily for a period of nine months. Seven patients received BRB powder (20g/3x/day) orally in water plus two suppositories (each composed of 700 mg BRB) that patients inserted into the rectum one hour before bedtime. The other seven patients were randomized to receive an oral placebo plus the two rectal suppositories. Rectal polyp counts were taken at time zero and after nine months of BRB treatment. The number of rectal polyps was reduced by a median of 43% at nine months overall including a median reduction of 59% in patients treated by both routes and 36% in patients treated with the suppositories only. Polyps and aberrant crypt foci, both were histopathologically identified as tubular adenomas, and adjacent normal tissues were collected both before and after berry treatment. Promoter methylation of CDKN2A, also known as p16, in collected specimens was measured using MassARRAY. Global methylation LINE-1 was determined by Pyrosequencing. MBDCap-seq genome-wide methylation analysis was used to discover other genes demethylated by berries. Further, the specimens were evaluated for p16, Ki-67, TUNEL, DNMT1 and DNMT3B expression by semi-quantitative immunohistochemistry. Our results showed that treatment with BRB powder, both orally and in the form of a BRB suppository, significantly reduced cell proliferation in the tubular adenomas. The suppository alone was sufficient to decrease promoter methylation of p16 leading to an increase in p16 protein expression in adjacent normal rectum and in tubular adenomas. This was associated with decreased protein expression of DNMT1 and DNMT3B. Based on MBDCap-seq data, BRBs significantly demethylated promoter CpGs of 44 genes in tubular adenomas. These genes are involved in the regulation of important cellular functions; e.g., cell proliferation, Wnt signaling and Notch pathway, etc. Lastly, berry treatment did not induce changes in global methylation LINE-1. In conclusion, our data provide evidence that one of the mechanisms for BRB-induced rectal polyp regression in FAP patients is through the demethylation and reactivation of tumor suppressor genes.(Supported by NCI grants CA148818 and CA103180, and USDA grant 38903-03560). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1009. doi:1538-7445.AM2012-1009
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- 2012
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