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Functional characterisation of tumour suppressor PDCD4 reveals a previously undisclosed role in the control of cell adhesion

ABSTRACT: PDCD4 is a multifunctional RNA binding protein which has tumour suppressor function. To more fully understand how dysregulation of this protein contributes to carcinogenesis we have carried out a comprehensive analysis of the role of PDCD4 in RNA metabolism in untransformed epithelial cells. We show that PDCD4 predominantly localises in the nucleus, where it interacts with proteins involved in a range of different RNA metabolic processes. We find that PDCD4 knockdown is associated with significant changes in either the expression or splicing of a number of transcripts, although it appears to have an indirect role in splicing. We identified the RNA targets of PDCD4 using iCLIP and observed an enrichment in binding to transcripts encoding cell adhesion and structural proteins. Consistent with these data, we show that PDCD4 acts as a general regulator of cell adhesion, which in a tumour setting would increase the metastatic potential of cells, and demonstrate that the nuclear localisation of PDCD4 is crucial in this process. Overall, the information obtained in untransformed cells provides new perspective for the role of PDCD4 as a tumour suppressor.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272497 | GEO | 2026/01/12

REPOSITORIES: GEO

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Functional characterisation of tumour suppressor PDCD4 reveals a previously undisclosed role in the control of cell adhesion

Project description:PDCD4 is a multifunctional RNA binding protein which has tumour suppressor function. To more fully understand how dysregulation of this protein contributes to carcinogenesis we have carried out a comprehensive analysis of the role of PDCD4 in RNA metabolism in untransformed epithelial cells. We show that PDCD4 predominantly localises in the nucleus, where it interacts with proteins involved in a range of different RNA metabolic processes. We find that PDCD4 knockdown is associated with significant changes in either the expression or splicing of a number of transcripts, although it appears to have an indirect role in splicing. We identified the RNA targets of PDCD4 using iCLIP and observed an enrichment in binding to transcripts encoding cell adhesion and structural proteins. Consistent with these data, we show that PDCD4 acts as a general regulator of cell adhesion, which in a tumour setting would increase the metastatic potential of cells, and demonstrate that the nuclear localisation of PDCD4 is crucial in this process. Overall, the information obtained in untransformed cells provides new perspective for the role of PDCD4 as a tumour suppressor.

2026-01-12 | GSE272498 | GEO

Neuronal activity promotes nuclear proteasome-mediated degradation of PDCD4 to regulate activity-dependent transcription in neurons

Project description:Activity-dependent gene expression is critical for synapse development and plasticity. To elucidate novel mechanisms linking neuronal activity to changes in transcription, we compared the nuclear proteomes of tetrodotoxin-silenced and bicuculline-stimulated cultured neurons using nuclear-localized APEX2 proximity biotinylation and mass spectrometry. The tumor suppressor protein PDCD4 was enriched in the nuclear proteome of silenced neurons, and PDCD4 levels rapidly decreased in the nucleus and cytoplasm of stimulated neurons. The activity-dependent decrease of PDCD4 was prevented by inhibitors of both PKC and proteasome activity and by a phospho-incompetent mutation of Ser71 in the βTRCP ubiquitin ligase-binding motif of PDCD4. We compared the activity-dependent transcriptomes of neurons expressing wildtype or degradation-resistant (S71A) PDCD4. We identified 91 genes as PDCD4 targets at the transcriptional level, including genes encoding proteins critical for synapse formation, remodeling, and transmission. Our findings indicate that regulated degradation of nuclear PDCD4 facilitates activity-dependent transcription in neurons.

2020-12-15 | GSE163127 | GEO

PLK1-mediated PDCD4 degradation confers resistance to enzalutamide in prostate cancer

Project description:Enzalutamide, a second-generation androgen receptor inhibitor, is utilized for treating patients with metastatic castration-resistant prostate cancer (mCRPC). However, acquired resistance to enzalutamide presents a significant clinical challenge, necessitating novel strategies for overcoming this resistance. In this study, we demonstrated that PLK1 phosphorylates PDCD4 at serine 239 (S239), leading to PDCD4 degradation by enhancing its binding to βTRCP2, thereby promoting enzalutamide resistance both in vitro and in vivo. Mechanistically, phosphorylation of PDCD4 at S239 upregulates the expression of UDP-glucuronosyltransferase 2B15 (UGT2B15) through activation of the c-MYC-Hedgehog axis. This pathway circumvents the androgen receptor, thereby reducing cellular sensitivity to enzalutamide treatment. Inhibition of UGT2B15 enhances enzalutamide-induced cell apoptosis and growth arrest in a manner dependent on PDCD4-S239 phosphorylation. Our findings provide a insight into the role of PLK1-mediated PDCD4 phosphorylation in enzalutamide resistance and suggest a potential therapeutic strategy to overcome resistance in prostate cancer.

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Analysis of PDCD4 knockdown effects by high throughput sequencing of a human epithelial cell line

Project description:Purpose: examination of gene expression and translation changes in immortalized human epithelial cells (hTERT-RPE-1) induced by PDCD4 siRNA-knockdown.

2020-01-20 | GSE138533 | GEO

Identification of cellular proteins binding to the 3’UTR of Programmed Cell Death 4 mRNA

Project description:The aim of the project is to identify RNA-binding proteins (RBPs) that interact with the 3’ untranslated region (3’UTR) of the programmed cell death 4 (PDCD4) mRNA. PDCD4 is an inflammatory tumor suppressor gene. The translation of PDCD4 mRNA is regulated by multiple RBPs. The aim is to identify RBPs which are critical for regulating PDCD4 mRNA translation by binding to its 3’UTR. For this purpose, a biotinylated PDCD4 3’UTR RNA was incubated with cytoplasmic lysate from MCF7 human breast carcinoma cells and the RNA-protein complexes pulled down by streptavidin affinity chromatography. The proteins were then eluted and resolved by SDS-PAGE. One particular protein band, migrating close to 55 KDa marker was cut out and submitted for proteomic analysis by in gel digestion and mass spectrometry.

2020-12-11 | PXD017376 | Pride

Long noncoding RNA EPCART regulates translation through PI3K/AKT/mTOR pathway and PDCD4 in prostate cancer

Project description:While hundreds of cancer-associate long noncoding RNAs (lncRNAs) have been discovered, their functional role in cancer cells is still a mystery for the majority of them. Increasing number of lncRNAs are recognized to function in the cytoplasm, including as modulators of translation. Here, we investigated the detailed molecular identity and functional role of EPCART, a lncRNA we previously discovered to be a potential oncogene in AR- and ERG-regulated prostate cancer (PCa) tumors. First, we confirmed EPCART to be a non-peptide-coding lncRNA with in silico methods and validated the transcript structure of EPCART in vitro. Pathway analysis of differentially expressed protein-coding genes in EPCART knockout cells implied EPCART to inhibit translational machinery of PCa cells. While drastic changes in the global translation were not detected in EPCART knockout cells by polysome profiling, EPCART located largely in the cytoplasm and at the sites of translation. With quantitative whole proteome studies on EPCART knockout cells we discovered PDCD4, an inhibitor of protein translation, to be increased by EPCART reduction. Further studies indicated that the inhibitory effect of EPCART on translation was mediated by reduced activation of AKT and inhibition of mTORC1 pathway. Together, our findings identify EPCART as a translation-associated lncRNA that functions via modulation of AKT/mTORC1/PDCD4 pathway in PCa cells. Furthermore, we provide evidence for prognostic potential of PDCD4 in PCa tumors in connection with EPCART.

2024-07-31 | GSE249960 | GEO

Proteomics exploiting modular baits with different subcellular locations reveal hydrogen peroxide-inducible clone 5 protein (HIC-5) and a glucocorticoid receptor variant as novel testin partners

Project description:The LIM domain and tumour suppressor protein Testin (Tes) is downregulated in a variety of human tumours and tumour cell lines. Depending on its conformation, Tes localises to stress fibres and focal adhesions where it forms protein complexes with other members of the actin cytoskeleton, such as zyxin and VASP, and thereby influences cellular processes like cell migration, adhesion or spreading. Tes is a modular protein and Tes variants lacking specific domains, localize to different locations in cells. To better understand the molecular basis of its function, we utilized an interaction proteomics approach combined with pathway analysis. This revealed proteins present in complexes in which Tes participates as a function of its modular structure as well as novel Tes interaction partners. We demonstrate that Tes interacts with a short isoform of the glucocorticoid receptor (GR), independently of the conventional full length GRα, a transcription factor important in regulating cellular metabolism and immune function. Tes also interacts with the focal adhesion protein and GR-coactivator Hic-5. In addition, we found that upon overexpression, Tes and Hic-5 induce opposite effects on cell spreading on a fibronectin matrix.

2018-10-26 | PXD005058 | Pride

PLK1-mediated PDCD4 degradation confers resistance to enzalutamide in prostate cancer

Project description:PLK1-mediated PDCD4 degradation confers resistance to enzalutamide in prostate cancer

| PRJNA1183556 | ENA

Exon arrays from HeLa cells transfected with RBM4-specific siRNA

Project description:RBM4 is a RNA-binding protein (RBP) able to modulate splicing by promoting exon inclusion and shares an import pathway with other splicing factors in the nucleus. In earlier studies we found that RBM4 interacts and colocalizes with WT1, which has been implicated in 10–15% of Wilms’ tumours and more recently in leukemya, is considered to be a tumour suppressor. RBM4, a RBP whose splicing effect is inhibited by the +KTS isoform of the tumour-suppressor/activator WT1, exhibits altered expression in different tumours, and may be essential for proliferation. Moreover, RBM4 binds to a number of RNAs of genes involved in acute myeloid leukaemia and cell cycle control. These results suggest that RBM4 may be involved in alternative splicing, tumorigenesis and particularly leukaemogenesis. To determine the endogenous transcripts that are targeted by RBM4 at the genome-wide level, we decided to perform exon microarray studies.

2012-07-15 | GSE32933 | GEO

Exon arrays from HeLa cells transfected with RBM4-specific siRNA

Project description:RBM4 is a RNA-binding protein (RBP) able to modulate splicing by promoting exon inclusion and shares an import pathway with other splicing factors in the nucleus. In earlier studies we found that RBM4 interacts and colocalizes with WT1, which has been implicated in 10M-bM-^@M-^S15% of WilmsM-bM-^@M-^Y tumours and more recently in leukemya, is considered to be a tumour suppressor. RBM4, a RBP whose splicing effect is inhibited by the +KTS isoform of the tumour-suppressor/activator WT1, exhibits altered expression in different tumours, and may be essential for proliferation. Moreover, RBM4 binds to a number of RNAs of genes involved in acute myeloid leukaemia and cell cycle control. These results suggest that RBM4 may be involved in alternative splicing, tumorigenesis and particularly leukaemogenesis. To determine the endogenous transcripts that are targeted by RBM4 at the genome-wide level, we decided to perform exon microarray studies. RBM4-specific siRNA has been used for knockdown of RBM4 in HeLa cells. RNA was extracted using a Qiagen RNA extraction kit from untransfected, mock and siRNA-transfected HeLa cells and quality of RNA for microarray analysis was checked using a Bioanalyzer 2100 (Agilent Technologies). Experiments were run in triplicates.

2012-07-14 | E-GEOD-32933 | biostudies-arrayexpress

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