Sungyong You | Cedars-Sinai Medical Center (original) (raw)

Papers by Sungyong You

ABSTRACT Prostate adenocarcinoma (PCa) is a leading cause of death from cancer and there is no ef... more ABSTRACT Prostate adenocarcinoma (PCa) is a leading cause of death from cancer and there is no effective treatment for castration−resistant disease. Transition from epithelial/mesenchymal to the amoeboid cancer cell phenotype evoked by loss of the cytoskeletal regulator Diaphanous related formin−3 (DIAPH3) results in invasive, metastatic behavior characterized by amoeboid migration and oncosome shedding. The objective of this study is to understand the mechanistic consequences of the amoeboid transition in PCa cells. Transcriptome expression in DU145 cells in which DIAPH3 was silenced was assessed using the Illumina HumanHT−12 V4.0 bead chip, and functional enrichment analysis of genes expressed differentially between DIAPH3 knockdown and control conditions was performed using DAVID software. A data mining framework was applied for identification of comprehensive functional associations arising from DIAPH3 deficiency using integration of heterogeneous biomedical knowledge base and gene expression profiles for DIAPH3 knockdown. Key transcription factor (TF)−target interaction data for 350 TFs derived from several databases were obtained using TRED, EEDB, mSigDB, Amadeus, bZIPDB, and OregAnno. Microarray analysis revealed 3,036 differential expressed genes (DEGs) in DIAPH3 deficient cells as compared to controls. Our computational analysis suggests that NFAT5 is a key transcription factor upregulated by DIAPH3 loss. Functional analyses indicate that NFAT5 controls a novel transcriptional program that mediates enhanced invasion in the setting of DIAPH3 depletion. DIAPH3 loss also leads to a significant reduction in expression of AKR1C1, a key enzyme that mediates the irreversible conversion of active androgen (5α−DHT) into the inactive 3β−Adiol. This finding suggests that DIAPH3 loss increases active androgen levels and may promote hormone refractory PCa through the de−regulation of AKR1C1. We have characterized the gene expression network that is perturbed in DU145 cells by DIAPH3 silencing and have found that NFAT5 and AKR1C1 are important signaling regulators perturbed by DIAPH3 loss. These findings provide insight into the potential clinical significance of the transition to the amoeboid tumor cell phenotype as well as a greater mechanistic understanding of the recently discovered link between DIAPH3 genomic loss, metastasis and castration−resistant PCa (Hager, Morley et al. EMBO Mol Med 2012).

Cancer research, Jan 14, 2016

Prostate cancer (PC) is a biologically heterogeneous disease with variable molecular alterations ... more Prostate cancer (PC) is a biologically heterogeneous disease with variable molecular alterations underlying cancer initiation and progression. Despite recent advances in understanding PC heterogeneity, better methods for classification of PC are still needed to improve prognostic accuracy and therapeutic outcomes. In this study we computationally assembled a large virtual cohort (n=1,321) of human PC transcriptome profiles from 38 distinct cohorts and, using pathway activation signatures of known relevance to PC, developed a novel classification system consisting of 3 distinct subtypes (named PCS1 to 3). We validated this subtyping scheme in 10 independent patient cohorts and 19 laboratory models of PC, including cell lines and genetically engineered mouse models. Analysis of subtype-specific gene expression patterns in independent datasets derived from luminal and basal cell models provides evidence that PCS1 and PCS2 tumors reflect luminal subtypes, while PCS3 represents a basal s...

Gene expression was profiled using Illumina HumanHT-12 V4.0. • Functional enrichment analysis of ... more Gene expression was profiled using Illumina HumanHT-12 V4.0. • Functional enrichment analysis of the shared DEGs was performed using DAVID software. • Data mining framework was applied for identification of comprehensive functional association related to DIAPH3 deficiency using integration of heterogeneous biomedical knowledge base and gene expression profiles for DIAPH3 knock-down, including 'Find Links' functionality of BioGraph. • To search key transcription factor (TF), 278,346 TF-target interaction data for the 350 TFs derived from several databases including TRED , EEDB, mSigDB, Amadeus, bZIPDB, and OregAnno were used. • Heatmap showing differential expression patterns of 3,036 DEGs in DIAPH3 deficient cells as compared to control cells. • Cellular processes enriched by 1,543 (Up) and 1,493 (Down) DEGs in DIAPH3 knock-down. • This context model suggests the possibility that lipid metabolic processes are affected by DIAPH3 knock-down via upregulation of SIRT1 expression.

American Journal of Respiratory and Critical Care Medicine, Nov 10, 2014

Nucleic Acids Research, 2002

AngioDB is a secondary database which brought data sources for a specific topic as angiogenesis f... more AngioDB is a secondary database which brought data sources for a specific topic as angiogenesis from primary database and additional literature resources. We firstly constructed AngioDB as Web-accessible database in 2000. It was remodelled with the integrated information according to the function from public databases. The current AngioDB contained 277 genes and 159 chemicals classified into 12 fields. The first version of AngioDB provided imagemap based-retrieving and database-derived information of a signaling network of angiogenesis-related biomolecules.

ABSTRACT Background: The androgen receptor (AR) is a transcription factor that employs many diver... more ABSTRACT Background: The androgen receptor (AR) is a transcription factor that employs many diverse interactions with coregulatory proteins in normal physiology and in prostate cancer (PCa). The AR mediates cellular responses in association with chromatin complexes and kinase cascades. Here we report that the nuclear matrix protein, scaffold attachment factor B (SAFB), regulates AR activity and AR levels in a manner that suggests its involvement in PCa. Methods: Oncomine and GENT database was used to investigate gene expression pattern of SAFB in cancer. Combined Outlier Analysis (COA) developed and applied to evaluate the significance of SAFB downregulation in metastatic PCa. Microarray analysis was performed to identify differentially expressed genes perturbed by SAFB silencing and their cellular functions using integrative hypothesis testing and DAVID software. A data integration approach was employed to select the potential SAFB target genes. Result: SAFB protein levels were reduced with disease progression in a cohort of human PCa that included metastatic tumors. SAFB mRNA expression was also lower in PCa in comparison to normal prostate tissue in a majority of publicly available RNA expression data sets. With these, COA result and copy number alteration show significance of reduced mRNA expression and loss of DNA content of SAFB is significant in metastatic PCa. Microarray analysis of SAFB silencing revealed strong association of SAFB function with androgen metabolism and epigenetic regulation. Knockdown of SAFB in androgen-dependent LNCaP PCa cells increased AR and prostate specific antigen (PSA) levels, stimulated growth of cultured cells and subcutaneous xenografts, and promoted a more aggressive phenotype, consistent with a repressive AR regulatory function. SAFB1 interacted with the histone methyltransferase EZH2 at AR-interacting chromatin sites. Based on combination of those three molecular signatures, 15 genes appear to be potential SAFB targets. Conclusion: Taken together, our results suggest that SAFB1 is a physiologically relevant co-repressor of AR and a novel functional partner of EZH2 and the PRC2 complex. SAFB1 and its associated proteins are an important node for the integration of signals through multiple oncogenic and tumor suppressor pathways in PCa and possibly other

Oncotarget, Jan 26, 2015

FYN is a SRC family kinase (SFK) that has been shown to be up-regulated in human prostate cancer ... more FYN is a SRC family kinase (SFK) that has been shown to be up-regulated in human prostate cancer (PCa) tissues and cell lines. In this study, we observed that FYN is strongly up-regulated in human neuroendocrine PCa (NEPC) tissues and xenografts, as well as cells derived from a NEPC transgenic mouse model. In silico analysis of FYN expression in prostate cancer cell line databases revealed an association with the expression of neuroendocrine (NE) markers such as CHGA, CD44, CD56, and SYP. The loss of FYN abrogated the invasion of PC3 and ARCaPM cells in response to MET receptor ligand HGF. FYN also contributed to the metastatic potential of NEPC cells in two mouse models of visceral metastasis with two different cell lines (PC3 and TRAMPC2-RANKL). The activation of MET appeared to regulate neuroendocrine (NE) features as evidenced by increased expression of NE markers in PC3 cells with HGF. Importantly, the overexpression of FYN protein in DU145 cells was directly correlated with th...

Journal of immunology (Baltimore, Md. : 1950), Jan 14, 2015

DNA methylation is an epigenetic mechanism that modulates gene expression in mammalian cells incl... more DNA methylation is an epigenetic mechanism that modulates gene expression in mammalian cells including T cells. Memory T cells are heterogeneous populations. Human effector memory (EM) CD8(+) T cells in peripheral blood contain two cell subsets with distinct traits that express low and high levels of the IL-7Rα. However, epigenetic mechanisms involved in defining such cellular traits are largely unknown. In this study, we use genome-wide DNA methylation and individual gene expression to show the possible role of DNA methylation in conferring distinct traits of chemotaxis and inflammatory responses in human IL-7Rα(low) and IL-7Rα(high) EM CD8(+) T cells. In particular, IL-7Rα(low) EM CD8(+) T cells had increased expression of CX3CR1 along with decreased DNA methylation in the CX3CR1 gene promoter compared with IL-7Rα(high) EM CD8(+) T cells. Altering the DNA methylation status of the CX3CR1 gene promoter changed its activity and gene expression. IL-7Rα(low) EM CD8(+) T cells had an i...

Scientific reports, Jan 16, 2015

Taxanes are widely employed chemotherapies for patients with metastatic prostate and breast cance... more Taxanes are widely employed chemotherapies for patients with metastatic prostate and breast cancer. Here, we show that loss of Diaphanous-related formin-3 (DIAPH3), frequently associated with metastatic breast and prostate cancers, correlates with increased sensitivity to taxanes. DIAPH3 interacted with microtubules (MT), and its loss altered several parameters of MT dynamics as well as decreased polarized force generation, contractility, and response to substrate stiffness. Silencing of DIAPH3 increased the cytotoxic response to taxanes in prostate and breast cancer cell lines. Analysis of drug activity for tubulin-targeted agents in the NCI-60 cell line panel revealed a uniform positive correlation between reduced DIAPH3 expression and drug sensitivity. Low DIAPH3 expression correlated with improved relapse-free survival in breast cancer patients treated with chemotherapeutic regimens containing taxanes. Our results suggest that inhibition of MT stability arising from DIAPH3 downr...

Neurourology and Urodynamics

This project will test the hypotheses that reduction or loss of expression of the chromatin scaff... more This project will test the hypotheses that reduction or loss of expression of the chromatin scaffold SAFB1 (1) promotes prostate cancer progression to advanced disease and (2) promotes castration-resistant prostate cancer in part through upregulation of cholesterol-dependent, intracrine androgen signaling. Figure 1. SAFB1 expression declines in a large fraction of human prostate cancer compared to normal prostate. (A) Outlier profile of SAFB1 expression in the Oncomine database. (B) Boxplots display SAFB1 expression pattern in normal and prostate cancer tissues. Abstract Methods Results Future Direction • Combined outlier analysis (COA) to interrogate changes in SAFB1 expression by collected publicly available data on prostate cancer (PCA) from the Oncomine and GENT databases. • Identification of genes regulated by SAFB1 through comparison of microarray data from SABF1-deficient and wild type LNCaP prostate cancer cells. • Identification of SAFB1 target genes using integrative hypot...

Oncotarget, Jan 14, 2015

Large oncosomes (LO) are atypically large (1-10µm diameter) cancer-derived extracellular vesicles... more Large oncosomes (LO) are atypically large (1-10µm diameter) cancer-derived extracellular vesicles (EVs), originating from the shedding of membrane blebs and associated with advanced disease. We report that 25% of the proteins, identified by a quantitative proteomics analysis, are differentially represented in large and nano-sized EVs from prostate cancer cells. Proteins enriched in large EVs included enzymes involved in glucose, glutamine and amino acid metabolism, all metabolic processes relevant to cancer. Glutamine metabolism was altered in cancer cells exposed to large EVs, an effect that was not observed upon treatment with exosomes. Large EVs exhibited discrete buoyant densities in iodixanol (OptiPrepTM) gradients. Fluorescent microscopy of large EVs revealed an appearance consistent with LO morphology, indicating that these structures can be categorized as LO. Among the proteins enriched in LO, cytokeratin 18 (CK18) was one of the most abundant (within the top 5th percentile)...

Database : the journal of biological databases and curation, 2015

Mammalian cells have cytoplasmic and mitochondrial aminoacyl-tRNA synthetases (ARSs) that catalyz... more Mammalian cells have cytoplasmic and mitochondrial aminoacyl-tRNA synthetases (ARSs) that catalyze aminoacylation of tRNAs during protein synthesis. Despite their housekeeping functions in protein synthesis, recently, ARSs and ARS-interacting multifunctional proteins (AIMPs) have been shown to play important roles in disease pathogenesis through their interactions with disease-related molecules. However, there are lacks of data resources and analytical tools that can be used to examine disease associations of ARS/AIMPs. Here, we developed an Integrated Database for ARSs (IDA), a resource database including cancer genomic/proteomic and interaction data of ARS/AIMPs. IDA includes mRNA expression, somatic mutation, copy number variation and phosphorylation data of ARS/AIMPs and their interacting proteins in various cancers. IDA further includes an array of analytical tools for exploration of disease association of ARS/AIMPs, identification of disease-associated ARS/AIMP interactors and...

BMB reports, Jan 31, 2008

Living organisms are comprised of various systems at different levels, i.e., organs, tissues, and... more Living organisms are comprised of various systems at different levels, i.e., organs, tissues, and cells. Each system carries out its diverse functions in response to environmental and genetic perturbations, by utilizing biological networks, in which nodal components, such as, DNA, mRNAs, proteins, and metabolites, closely interact with each other. Systems biology investigates such systems by producing comprehensive global data that represent different levels of biological information, i.e., at the DNA, mRNA, protein, or metabolite levels, and by integrating this data into network models that generate coherent hypotheses for given biological situations. This review presents a systems biology framework, called the 'Integrative Proteomics Data Analysis Pipeline' (IPDAP), which generates mechanistic hypotheses from network models reconstructed by integrating diverse types of proteomic data generated by mass spectrometry-based proteomic analyses. The devised framework includes a ...

Experimental & Molecular Medicine, 2014

Chronic neuroinflammation is an integral pathological feature of major neurodegenerative diseases... more Chronic neuroinflammation is an integral pathological feature of major neurodegenerative diseases. The recruitment of microglia to affected brain regions and the activation of these cells are the major events leading to disease-associated neuroinflammation. In a previous study, we showed that neuron-released a-synuclein can activate microglia through activating the Toll-like receptor 2 (TLR2) pathway, resulting in proinflammatory responses. However, it is not clear whether other signaling pathways are involved in the migration and activation of microglia in response to neuron-released a-synuclein. In the current study, we demonstrated that TLR2 activation is not sufficient for all of the changes manifested by microglia in response to neuronreleased a-synuclein. Specifically, the migration of and morphological changes in microglia, triggered by neuron-released a-synuclein, did not require the activation of TLR2, whereas increased proliferation and production of cytokines were strictly under the control of TLR2. Construction of a hypothetical signaling network using computational tools and experimental validation with various peptide inhibitors showed that b1-integrin was necessary for both the morphological changes and the migration. However, neither proliferation nor cytokine production by microglia was dependent on the activation of b1-integrin. These results suggest that b1-integrin signaling is specifically responsible for the recruitment of microglia to the diseaseaffected brain regions, where neurons most likely release relatively high levels of a-synuclein.