Androgen regulated ECD overexpression promotes prostate cancer tumorigenesis through increased glycolysis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE287898 | GEO | 2025/12/02
REPOSITORIES: GEO
Similar Datasets
Project description:Purpose: To study the expression and function of a novel cell cycle regulatory protein, human ecdysoneless (Ecd), during pancreatic cancer (PC) pathogenesis. Experimental Design: Immunohistochemical expression profiling of Ecd was done in non-neoplastic normal pancreatic tissues and pancreatic ductal adenocarcinoma lesions (from tissue microarray and Rapid Autopsy program) as well as precancerous PanIN lesions and metastatic organs. To analyze the biological significance of Ecd in PC progression, Ecd was stably knocked down in PC cell line followed by in vitro and in vivo functional assays. Results: Normal pancreatic ducts show very weak to no Ecd expression compared to significant positive expression in PC tissues (mean±SE composite score: 0.3±0.2 and 3.8±0.2 respectively, p<0.0001) as well as in PanIN precursor lesions with a progressive increase in Ecd expression with increasing dysplasia (PanIN-1 to PanIN-3). Analysis of matched primary tumors and metastases from PC patients revealed that Ecd is highly expressed in both primary pancreatic tumor and in distant metastatic sites. Further, knockdown of Ecd suppressed cell proliferation in vitro and tumorigenicity of PC cells in mice orthotopic tumors. Microarray study revealed that Ecd regulates expression of glucose transporter GLUT4 in PC cells and was subsequently shown to modulate glucose uptake, lactate production and ATP generation by PC cells. Finally, knockdown of Ecd also reduced level of pAkt, key signaling molecule known to regulate aerobic glycolysis in cancer cells. Conclusion: Ecd is a novel tumor promoting factor that is differentially expressed in pancreatic cancer and potentially regulates glucose metabolism within cancer cells. Two-condition experiment, Ecd knockdown vs Scrambled cells. Biological replicates: 3 Ecd knockdownl, 3 Scrambled, independently grown and harvested. One replicate per array
2012-08-09 | E-GEOD-39988 | biostudies-arrayexpress
Project description:Purpose: To study the expression and function of a novel cell cycle regulatory protein, human ecdysoneless (Ecd), during pancreatic cancer (PC) pathogenesis. Experimental Design: Immunohistochemical expression profiling of Ecd was done in non-neoplastic normal pancreatic tissues and pancreatic ductal adenocarcinoma lesions (from tissue microarray and Rapid Autopsy program) as well as precancerous PanIN lesions and metastatic organs. To analyze the biological significance of Ecd in PC progression, Ecd was stably knocked down in PC cell line followed by in vitro and in vivo functional assays. Results: Normal pancreatic ducts show very weak to no Ecd expression compared to significant positive expression in PC tissues (mean±SE composite score: 0.3±0.2 and 3.8±0.2 respectively, p<0.0001) as well as in PanIN precursor lesions with a progressive increase in Ecd expression with increasing dysplasia (PanIN-1 to PanIN-3). Analysis of matched primary tumors and metastases from PC patients revealed that Ecd is highly expressed in both primary pancreatic tumor and in distant metastatic sites. Further, knockdown of Ecd suppressed cell proliferation in vitro and tumorigenicity of PC cells in mice orthotopic tumors. Microarray study revealed that Ecd regulates expression of glucose transporter GLUT4 in PC cells and was subsequently shown to modulate glucose uptake, lactate production and ATP generation by PC cells. Finally, knockdown of Ecd also reduced level of pAkt, key signaling molecule known to regulate aerobic glycolysis in cancer cells. Conclusion: Ecd is a novel tumor promoting factor that is differentially expressed in pancreatic cancer and potentially regulates glucose metabolism within cancer cells.
2012-08-10 | GSE39988 | GEO
Project description:Androgen regulated ECD overexpression promotes prostate cancer tumorigenesis through increased glycolysis
| PRJNA1214886 | ENA
Project description:The mammalian orthologue of the Drosophila ecdysoneless (ECD) mRNA and protein are overexpressed in breast cancer, and its overexpression correlates with poor prognosis and short patient survival, particularly in ERBB2/HER2-positive breast cancer (BC). This work investigates the co-operative oncogenic mechanism of ECD and ERBB2 by deriving transgenic mice overexpressing ECD and/or ERBB2 (huHER2) in mammary epithelium under MMTV promoter (ECD+HER2Tg), as well as human mammary immortal epithelial cell lines (hMECs) overexpressing ECD and/or ERBB2. While huHER2Tg mice developed more homogenous solid nodular carcinomas, double transgenic mice (ECD; huHER2Tg) developed heterogenous and histologically aggressive mammary tumors with basal-like phenotype and epithelial mesenchymal transition (EMT) features, similar to ECDTg tumors. Importantly, transcriptomic profile of ECD; huHER2Tg tumors revealed upregulation of two major oncogenic pathways, unfolded protein response (UPR) and glycolysis. Consistently, ECD; huHER2Tg tumors exhibited increased mRNA levels of cancer stem cell markers and EMT related genes. Further, hMECs expressing both ECD and ERBB2 as compared to ECD or ERBB2 expressing cells showed significant increase in oncogenic traits, such as enhanced migration, anchorage independence, mammosphere, and organoid formation. RNA sequencing analysis of single and double transfectants showed significant upregulation of glycolysis and UPR pathways in ECD+ERBB2 expressing cells as compared to ECD or ERBB2 overexpressing hMECs. Given our recent finding that ECD directly binds to RNA, we demonstrate mRNAs of three key glycolytic enzymes (LDHA, PKM2 and HK2) and mRNA of a major UPR regulated gene GRP78 directly associated with ECD protein using RNA immunoprecipitation assay. Higher expression of glycolytic mRNAs and GRP78 in ECD+ERBB2-expressing cells was due to increased mRNA stability. Lastly, we show an increase in glucose uptake and enhanced glycolytic rate in ECD+ERBB2-overexpressing cells as compared to ECD- or ERBB2-overexpressing hMECs. Taken together, our findings support a co-operative role of ECD and ERBB2 in oncogenesis by enhancing two major oncogenic pathways, UPR and glycolysis. These results provide experimental proof and mechanistic insights to our previous findings that ECD is overexpressed in ERBB2-positive BC patients, and its’ overexpression correlates with poor prognosis and short survival in patients.
2026-01-20 | GSE287075 | GEO
Project description:Identification of the interaction partners of the protein ecdysoneless (Ecd) in Drosophila melanogaster S2 cells as well as profiling of the changes in binding for mutant, truncated Ecd del34 protein.
2021-09-09 | PXD019838 | Pride
Project description:Overexpression of ECD in mammary gland promotes mammary tumorigenesis. To determine the plausible mechanism of how ECD contributes the oncogenesis, we performed RNAseq analysis of three independent control mice mammary glands (6 months old) and four independent ECD transgenic mammary tumors. Out of these four tumors, T1a and T1b were adenosquamous carcinoma type, T3 was Spindle cell carcinoma type and T4 was papillary carcinoma. RNA was isolated from the respective samples and RNAseq was performed.
2022-05-18 | GSE200838 | GEO
Project description:The aberrant expression of androgen receptor (AR)-dependent transcriptional programs is a defining pathology of the development and progression of prostate cancers. Transcriptional cofactors that bind AR are critical determinants of prostate tumorigenesis. To gain a deeper understanding of the proteins linked to AR-dependent gene transcription, we performed a DNAaffinity chromatography-based proteomic screen designed to identify proteins involved in ARmediated gene transcription in prostate tumor cells.
2015-09-03 | PXD002596 | Pride
Project description:The androgen receptor (AR) is a key driver of prostate cancer (PC), even in the state of castration-resistant PC (CRPC), and frequently even after treatment with second-line hormonal therapies such as abiraterone and enzalutamide. The persistence of AR activity via both ligand-dependent and ligand-independent (including constitutively active AR splice variants) mechanisms highlights the unmet need for alternative approaches to block AR signaling in CRPC. We investigated the transcription factor GATA2 as a regulator of AR signaling and a novel therapeutic target in PC. We demonstrate that GATA2 directly promotes AR expression (both full-length and splice variant), resulting in a strong positive correlation between GATA2 and AR expression in PC (cell lines and patient specimens). Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of AR (both full-length and splice variant). GATA2 co-localizes with AR and FOXA1 on chromatin to enhance recruitment of steroid receptor coactivators (SRCs) and formation of the transcriptional holocomplex. In agreement with these important functions, high GATA2 expression and transcriptional activity predicted for worse clinical outcome in PC patients. A GATA2 small molecule inhibitor suppressed the expression and transcriptional function of AR (both full-length and splice variant) and exerted potent anticancer activity against PC cell lines. We propose pharmacological inhibition of GATA2 as a “first-in-field” approach to target AR expression and function and improve outcomes in CRPC. LNCaP cells were transfected with control siRNA (3), GATA2 siRNA (3) or AR siRNA for 72 hours.
2015-01-21 | E-GEOD-63539 | biostudies-arrayexpress
Project description:Androgen receptor (AR) is overexpressed in the majority of castration-resistant prostate cancers (CRPCs). Our goal was to study the effect of AR overexpression on the chromatin binding of the receptor and to identify AR target genes that may be important in the emergence of CRPC. We have established two sublines of LNCaP prostate cancer (PC) cell line, one overexpressing AR 2M-bM-^@M-^S3-fold and the other 4M-bM-^@M-^S5-fold compared with the control cells. We used chromatin immunoprecipitation (ChIP) and deep-sequencing (seq) to identify AR-binding sites (ARBSs). We found that the number of ARBSs and the AR-binding strength were positively associated with the level of AR when cells were stimulated with low concentrations of androgens. In cells overexpressing AR, the chromatin binding of the receptor took place in 100-fold lower concentration of the ligand than in control cells. We conM-oM-,M-^Armed the association of AR level and chromatin binding in two PC xenografts, one containing AR gene ampliM-oM-,M-^Acation with high AR expression, and the other with low expression. By combining the ChIP-seq and expression proM-oM-,M-^Aling, we identiM-oM-,M-^Aed AR target genes that are upregulated in PC. Of them, the expression of ZWINT, SKP2 (S-phase kinase-associated protein 2 (p45)) and FEN1 (M-oM-,M-^Bap structure-speciM-oM-,M-^Ac endonuclease 1) was demonstrated to be increased in CRPC, while the expression of SNAI2 was decreased in both PC and CRPC. FEN1 protein expression was also associated with poor prognosis in prostatectomy-treated patients. Finally, the knock-down of FEN1 with small interfering RNA inhibited the growth of LNCaP cells. Our data demonstrate that the overexpression of AR sensitizes the receptor binding to chromatin, thus, explaining how AR signaling pathway is reactivated in CRPC cells. Examination of AR binding with 9 cell line samples + control and 2 xenograft samples + control. ChIPseq with AR antibody in 3 different LNCaP derivative cell lines overexpressing AR upon treatment with different androgen concentrations and 2 different tumor xenografts expressing different AR levels.
2013-06-27 | E-GEOD-48308 | biostudies-arrayexpress
Project description:Androgen receptor (AR) is a key player in prostate cancer development and progression. Here we applied immunoprecipitation mass spectrometry of endogenous AR in LNCaP cells to identify components of the AR transcriptional complex. In total, 66 known and novel AR interactors were identified in the presence of synthetic androgen, most of which were critical for AR-driven prostate cancer cell proliferation. A subset of AR interactors required for LNCaP proliferation were profiled using chromatin immunoprecipitation assays followed by sequencing, identifying distinct genomic subcomplexes of AR interaction partners. Interestingly, three major subgroups of genomic subcomplexes were identified, where selective gain of function for AR genomic action in tumorigenesis was found, dictated by FOXA1 and HOXB13. In summary, by combining proteomic and genomic approaches we reveal subclasses of AR transcriptional complexes, differentiating normal AR behavior from the oncogenic state. In this process, the expression of AR interactors has key roles by reprogramming the AR cistrome and interactome in a genomic location-specific manner.
2017-10-27 | PXD008056 | Pride