SENP2 regulates MMP13 expression in a bladder cancer cell line through SUMOylation of TBL1/TBLR1.
Ontology highlight
ABSTRACT:
SUBMITTER: Tan M
PROVIDER: S-EPMC4570209 | biostudies-other | 2015 Sep
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Background:Bladder cancer remains a cancer type in need of novel and alternative therapies. While multiple inhibitors of EGFR have been evaluated for efficacy in bladder cancer, the results have largely been disappointing with few patients responding to these therapies. Yet, there is a subset of patients that positively responds to EGFR inhibition with tumor shrinkage, indicating it is an effective treatment for a targeted set of bladder tumors. Objective:To derive a gene expression signature capable of predicting the response to EGFR inhibition in bladder cancer cell lines. Methods:he response to cetuximab for 68 colorectal cancer patients was used as training data to generate a gene expression signature. We applied this signature to bladder cancer cell lines and predictions were compared to the responses to seven EGFR inhibitors. Results:A novel 67-gene signature derived from colorectal cancer was able to significantly identify bladder cancer cell lines by their response to several EGFR inhibitors. Conclusions:The 67-gene signature can determine bladder cancer cell line sensitivity to EGFR inhibition. This work demonstrates a preclinical strategy to identify bladder cancer cell lines for EGFR-targeted therapy.
| S-EPMC6087449 | biostudies-literature
Project description:The androgen receptor (AR) is important in the development of both experimental and human bladder cancer. However, the role of AR in bladder cancer growth and progression is less clear, with literature indicating that more advanced stage and grade disease are associated with reduced AR expression. To determine the mechanisms underlying these relationships, we profiled AR-expressing human bladder cancer cells by AR chromatin immunoprecipitation sequencing and complementary transcriptomic approaches in response to in vitro stimulation by the synthetic androgen R1881. In vivo functional genomics consisting of pooled shRNA or pooled open reading frame libraries was employed to evaluate 97 genes that recapitulate the direction of expression associated with androgen stimulation. Interestingly, we identified CD44, the receptor for hyaluronic acid, a potent biomarker and driver of progressive disease in multiple tumor types, as significantly associated with androgen stimulation. CRISPR-based mutagenesis of androgen response elements associated with CD44 identified a novel silencer element leading to the direct transcriptional repression of CD44 expression. In human patients with bladder cancer, tumor AR and CD44 mRNA and protein expression were inversely correlated, suggesting a clinically relevant AR-CD44 axis. Collectively, our work describes a novel mechanism partly explaining the inverse relationship between AR and bladder cancer tumor progression and suggests that AR and CD44 expression may be useful for prognostication and therapeutic selection in primary bladder cancer. SIGNIFICANCE: This study describes novel AREs that suppress CD44 and an expected inverse correlation of AR-CD44 expression observed in human bladder tumors.
| S-EPMC8782536 | biostudies-literature
Project description:Mutations in the gene encoding the transcription factor forkhead box P2 (FOXP2) result in brain developmental abnormalities, including reduced gray matter in both human patients and rodent models and speech and language deficits. However, neither the region-specific function of FOXP2 in the brain, in particular the cerebellum, nor the effects of any posttranslational modifications of FOXP2 in the brain and disorders have been explored.We characterized sumoylation of FOXP2 biochemically and analyzed the region-specific function and sumoylation of FOXP2 in the developing mouse cerebellum. Using in utero electroporation to manipulate the sumoylation state of FOXP2 as well as Foxp2 expression levels in Purkinje cells of the cerebellum in vivo, we reduced Foxp2 expression approximately 40% in the mouse cerebellum. Such a reduction approximates the haploinsufficiency observed in human patients who demonstrate speech and language impairments.We identified sumoylation of FOXP2 at K674 (K673 in mice) in the cerebellum of neonates. In vitro co-immunoprecipitation and in vivo colocalization experiments suggest that PIAS3 acts as the small ubiquitin-like modifier E3 ligase for FOXP2 sumoylation. This sumoylation modifies transcriptional regulation by FOXP2. We demonstrated that FOXP2 sumoylation is required for regulation of cerebellar motor function and vocal communication, likely through dendritic outgrowth and arborization of Purkinje cells in the mouse cerebellum.Sumoylation of FOXP2 in neonatal mouse cerebellum regulates Purkinje cell development and motor functions and vocal communication, demonstrating evidence for sumoylation in regulating mammalian behaviors.
| S-EPMC4983264 | biostudies-literature
Project description:Elevated expression of EZH2, the enzymatic subunit of polycomb repressive complex 2 (PRC2), often occurs in cancer. EZH2 expression results in the silencing of genes that suppress tumor formation and metastasis through trimethylation of histone H3 at lysine 27 (H3K27me3) at their promoters. However, inhibitors of EZH2 enzymatic activity have not shown the expected efficacy against cancer in clinical trials, suggesting a need for other strategies to address EZH2 overexpression. Here, we show that SUMOylation, a posttranslational modification characterized by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a lysine (Lys) residue on target proteins, enhances EZH2 transcription. Either knockdown of the SUMO-activating enzyme SAE2 or pharmacologic inhibition of SUMOylation resulted in decreased levels of EZH2 mRNA and protein as well as reduced H3K27me3 levels. SUMOylation regulated EZH2 expression by enhancing binding of the E2F1 transcriptional activator to the EZH2 promoter. Inhibition of SUMOylation not only resulted in reduced EZH2 mRNA and protein levels but also increased expression of genes silenced by EZH2, such as E-cadherin, which suppresses epithelial-mesenchymal transition and metastasis. In more than 6,500 patient tumor samples across different cancer types, expression of UBA2 and EZH2 was positively correlated. Taken together, our findings suggest that inhibition of SUMOylation may serve as a potential strategy to address EZH2 overexpression and improve current cancer therapeutic approaches. SIGNIFICANCE: These findings provide important biological insights into the mechanism of EZH2 overexpression in cancers and suggest that inhibiting SUMOylation may improve current cancer therapeutic approaches.
| S-EPMC8741410 | biostudies-literature
Project description:In this research, Human OneArray Microarray analysis was performed to obtain broad spectrum information about the genes differentially expressed in human bladder cancer cell line RT112 and Gemcitabine Resistant Bladder Cancer cell line RT112-Gr.
2015-04-16 | E-MTAB-3495 | biostudies-arrayexpress
Project description:The coiled coil is a superhelical structural protein motif involved in a diverse array of biological functions, and the abnormal expression of the coiled-coil domain containing proteins has a direct link with the phenotype of tumor cell migration, invasion and metastasis. The aim of this study was to investigate the critical role of Coiled-coil domain-containing protein 34 (CCDC34) in bladder carcinogenesis, which has never been reported to date. Here, we found CCDC34 expression was elevated in bladder cancer tissues and cell lines. The knockdown of CCDC34 via lentivirus-mediated siRNA significantly suppressed bladder cancer cells proliferation and migration, and induced cell cycle arrest at G2/M phase and increased apoptosis in vitro. In addition, CCDC34 knockdown suppressed bladder tumor growth in nude mice. Moreover, CCDC34 silencing decreased the phosphorylation of MEK, ERK1/2, JNK, p38 and Akt, and the expressions of c-Raf and c-Jun, indicating MAPK and AKT pathways (ERK/MAPK, p38/MAPK, JNK/MAPK and PI3K/Akt) might be involved in CCDC34 regulation of bladder cancer cell proliferation and migration. Our findings revealed for the first time a potential oncogenic role for CCDC34 in bladder carcinoma pathogenesis and it may serve as a biomarker or even a therapeutic target for bladder cancer.
| S-EPMC4694871 | biostudies-other
Project description:AMP-activated protein kinase (AMPK) is the central metabolic regulator of the cell and controls energy consumption based upon nutrient availability. Due to its role in energy regulation, AMPK has been implicated as a barrier for cancer progression and is suppressed in multiple cancers. To examine whether AMPK regulates bladder cancer cell growth, HTB2 and HT1376 bladder cells were treated with an AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). AICAR treatment reduced proliferation and induced the expression of p27Kip1 (CDKN1B), which was mediated through an mTOR-dependent mechanism. Interestingly, AMPKα2 knockdown resulted in reduced p27 levels, whereas AMPKα1 suppression did not. To further determine the exact mechanism by which AMPKa2 regulates p27, HTB2 and HT1376 cells were transduced with an shRNA targeting AMPKα2. Stable knockdown of AMPKα2 resulted in increased proliferation and decreased p27 protein. The reduced p27 protein was determined to be dependent upon SKP2. Additionally, loss of AMPKα2 in a xenograft and a chemical carcinogen model of bladder cancer resulted in larger tumors with less p27 protein and high SKP2 levels. Consistent with the regulation observed in the bladder cancer model systems, a comprehensive survey of human primary bladder cancer clinical specimens revealed low levels of AMPKα2 and p27 and high levels of SKP2.ImplicationsThese results highlight the contribution of AMPKα2 as a mechanism for controlling bladder cancer growth by regulating proliferation through mTOR suppression and induction of p27 protein levels, thus indicating how AMPKα2 loss may contribute to tumorigenesis. Mol Cancer Res; 14(12); 1182-94. ©2016 AACR.
| S-EPMC5136331 | biostudies-literature
Project description:BackgroundBladder cancer is having a gradually increasing incidence in China. Except for the traditional chemotherapy drugs, there are no emerging new drugs for almost 30 years in bladder cancer. New potential therapeutic targets and biomarkers are urgently needed.MethodsBORA is the activator of kinase Aurora A and plays an important role in cell cycle progression. To investigate the function of BORA in BCa, we established BORA knockdown and overexpression cell models for in vitro studies, xenograft and pulmonary metastasis mouse models for in vivo studies.ResultsOur results indicated that BORA was upregulated in human bladder cancer (BCa) compared to the normal bladder and paracancerous tissues at transcriptional and translational levels. We found that BORA was positively related to BCa cell proliferation. Furthermore, BORA knockdown induced cell cycle arrest in G2/M phase while BORA overexpression decreased the proportion of cells in G2/M, associated with PLK1-CDC25C-CDK1 alteration. Interestingly, we observed that knockdown of BORA inhibited BCa cell migration and invasion, accompanied with alterations of epithelial-mesenchymal transition (EMT) pathway related proteins. In vivo studies confirmed the inhibition effect of BORA knockdown on BCa cell growth and migration.ConclusionsOur study indicates that BORA regulates BCa cell cycle and growth, meanwhile influences cell motility by EMT, and could be a novel biomarker and potential therapeutic target in BCa.
| S-EPMC7339433 | biostudies-literature
Project description:The mammalian small ubiquitin-like modifiers (SUMOs) are actively involved in regulating differentiation of different cell types. However, the functional differences between SUMO isoforms and their mechanisms of action remain largely unknown. Using the ocular lens as a model system, we demonstrate that different SUMOs display distinct functions in regulating differentiation of epithelial cells into fiber cells. During lens differentiation, SUMO1 and SUMO2/3 displayed different expression, localization, and targets, suggesting differential functions. Indeed, overexpression of SUMO2/3, but not SUMO1, inhibited basic (b) FGF-induced cell differentiation. In contrast, knockdown of SUMO1, but not SUMO2/3, also inhibited bFGF action. Mechanistically, specificity protein 1 (Sp1), a major transcription factor that controls expression of lens-specific genes such as ?-crystallins, was positively regulated by SUMO1 but negatively regulated by SUMO2. SUMO2 was found to inhibit Sp1 functions through several mechanisms: sumoylating it at K683 to attenuate DNA binding, and at K16 to increase its turnover. SUMO2 also interfered with the interaction between Sp1 and the coactivator, p300, and recruited a repressor, Sp3 to ?-crystallin gene promoters, to negatively regulate their expression. Thus, stable SUMO1, but diminishing SUMO2/3, during lens development is necessary for normal lens differentiation. In support of this conclusion, SUMO1 and Sp1 formed complexes during early and later stages of lens development. In contrast, an interaction between SUMO2/3 and Sp1 was detected only during the initial lens vesicle stage. Together, our results establish distinct roles of different SUMO isoforms and demonstrate for the first time, to our knowledge, that Sp1 acts as a major transcription factor target for SUMO control of cell differentiation.
| S-EPMC3992630 | biostudies-literature
Project description:BackgroundWe previously demonstrated that AIB1 overexpression is an independent molecular marker for shortened survival of bladder cancer (BC) patients. In this study, we characterised the role and molecular mechanisms of AIB1 in BC tumorigenicity.MethodsAIB1 expression was measured by immunohistochemistry in non-muscle-invasive BC tissue and adjacent normal bladder tissue. In addition, the tumorigenicity of AIB1 was assessed with in vitro and in vivo functional assays.ResultsOverexpression of AIB1 was observed in tissues from 46 out of 146 patients with non-muscle-invasive BC and was an independent predictor for poor progression-free survival. Lentivirus-mediated AIB1 knockdown inhibited cell proliferation both in vitro and in vivo, whereas AIB1 overexpression promoted cell proliferation in vitro. The growth-inhibitory effect induced by AIB1 knockdown was mediated by G1 arrest, which was caused by reduced expression of key cell-cycle regulatory proteins through the AKT pathway and E2F1.ConclusionOur results suggest that AIB1 promotes BC cell proliferation through the AKT pathway and E2F1. Furthermore, AIB1 overexpression predicts tumour progression in patients with non-muscle-invasive BC.
| S-EPMC3629431 | biostudies-literature