Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

An epigenetically-deregulated tumor state reveals a new role for embryonic transcription factors as cancer drivers

ABSTRACT: Tumor initiation is often linked to a loss of cellular identity. Transcriptional programs determining cellular identity are preserved by epigenetically-acting chromatin factors. Although such regulators are among the most frequently mutated genes in cancer, it is not well understood how an aberration of the epigenetic status contributes to tumor onset. In this work, we investigated the transcriptional signature of tumors caused by disruption of the Drosophila epigenetic regulator, polyhomeotic (ph). In larval tissue, ph mutant cells show a shift towards an embryonic-like signature. Using loss- and gain-of-function experiments, we uncovered the embryonic transcription factor knirps (kni) as a new cancer driver. The oncogenic potential of kni lies in its ability to activate JAK/STAT signaling and block differentiation. Conversely, tumor growth in ph mutant cells can be substantially reduced by overexpressing a differentiation factor. This demonstrates that epigenetically derailed tumor conditions can be reversed by induction of differentiation.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE101463 | GEO | 2018/03/20

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Genome wide analysis of binding of Polyhomeotic and polymerization defective Polyhomeotic in Drosophila S2 cells

Project description:To understand the role of the conserved Sterile Alpha Motif of the Polycomb Group protein Polyhomeotic, the genome wide distribution of wild type and polymerization defective Polyhomeotic containing mutations in the SAM domain was determined by ChIP-SEQ. ChIP-seq Identification of polyhomeotic wild type (PH-WT) and mutant (PH-ML) binding sites.

2016-03-08 | E-GEOD-60686 | biostudies-arrayexpress

Knockdown of Polyhomeotic in Drosophila Kc cells

Project description:In this experiment, we used RNAi targeting both copies of the gene polyhomeotic (ph-p and ph-d) to knockdown expression of this factor in Drosophila Kc167 cells. We observed substantial changes to the structure of genomic loci bound by Polycomb-group proteins as assayed by single-molecule based super-resolution imaging with STORM. We also observed a substantial de-repression of many genes which reside in Polycomb-bound domains, as assayed with RNA-seq.

2015-11-20 | GSE75060 | GEO

Knockdown of Polyhomeotic in Drosophila Kc cells

2015-11-20 | E-GEOD-75060 | biostudies-arrayexpress

An intrinsic tumor-suppression mechanism mediated by steroid hormone in Drosophila

Project description:Polycomb group (PcG) proteins are evolutionarily conserved epigenetic regulators that mediate histone modifications and suppress target gene expression, therefore establish and maintain cellular memory during development1-3. Deregulation of PcG genes is associated with various human cancers, but the mechanisms are incompletely understood4. Polyhomeotic (Ph), one of the Drosophila PcG proteins, can act as a tumor suppressor in larval imaginal discs5, 6. Cells mutant for ph overgrow and give rise to neoplastic tumors during larval development6. Here we report an intrinsic tumor-suppression mechanism mediated by the steroid hormone ecdysone in Drosophila. During metamorphosis, ecdysone transforms tumorigenic ph mutant cells into non-tumorigenic cells, thereby suppressing the malignant growth in adult flies. We demonstrate ecdysone exerts its function by inducing the expression of microRNA lethal-7 (let-7), which suppresses its target gene chinmo, to inhibit the tumorigenic growth of ph mutant cells. Furthermore, we show let-7 can also suppress the overgrowth of brain tumors in brain tumor (brat) mutant flies, indicating this intrinsic mechanism is functional in different tissues to suppress neoplastic growth. As let-7 is highly conserved among metazoans, our findings will be relevant for mechanistic studies and therapeutic applications in human cancers.

2018-08-20 | GSE101455 | GEO

Genome wide analysis of binding of Polyhomeotic and polymerization defective Polyhomeotic in Drosophila S2 cells

2016-03-08 | GSE60686 | GEO

The effects of PTIP on Polycomb mediated repression in Drosophila Kc167 cells.

Project description:Drosophila Kc167 cells were used to test the function of PTIP in regulating gene expression before and after loss of polycomb function. Four condtions were tested using dsRNA knockdowns (RNAi) Experiment Overall Design: Kc167 cells alone, Kc cells with loss of PTIP, cells with loss of polycomb and polyhomeotic, and cells with loss of PTIP, polycomb, and polyhomeotic. Performed in triplicate.

2009-03-15 | E-GEOD-15092 | biostudies-arrayexpress

Acid-base homeostasis orchestrated by NHE1 defines the pancreatic stellate cell phenotype in pancreatic cancer

Project description:Pancreatic ductal adenocarcinoma (PDAC) progresses in an organ with a unique pH landscape, where the stroma acidifies after each meal. We hypothesized that disrupting this pH landscape during PDAC progression triggers pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs) to induce PDAC fibrosis. We revealed that alkaline environmental pH is sufficient to induce PSC differentiation to a myofibroblastic phenotype. We then mechanistically dissected this finding focusing on the involvement of the Na+/H+ exchanger NHE1. Perturbing cellular pH homeostasis by inhibiting NHE1 with cariporide partially alters the myofibroblastic PSC phenotype. To show the relevance of this finding in vivo, we targeted NHE1 in murine PDAC (KPfC). Indeed, tumor fibrosis decreases when mice receive the NHE1-inhibitor cariporide in addition to gemcitabine treatment. Moreover, the tumor immune infiltrate shifts from granulocyte-rich to more lymphocytic. Taken together, our study provides mechanistic evidence on how the pancreatic pH landscape shapes pancreatic cancer through tuning PSC differentiation.

2023-09-18 | GSE223205 | GEO

TWIST2-Mediated Chromatin Remodeling Promotes Fusion-Negative Rhabdomyosarcoma [RNA-seq FN-RMS Cells]

Project description:Sarcomas are derailed in pathways that specify mesenchymal lineages during embryogenesis, causing tumor cells to stall at early stages of differentiation. Among them, rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma of skeletal muscle origin. A key feature of RMS is their inability to terminally differentiate despite the high expression of master myogenic regulator MYOD. The bHLH transcription factor TWIST2, which governs mesenchymal stem cell identity and restricts myogenesis, is overexpressed in patient fusion-negative RMS (FN-RMS) tumors. We show that knockdown of TWIST2 enables FN-RMS cells to exit the cell cycle and undergo myogenic differentiation, thereby reducing the growth of FN-RMS xenograft tumors. ChIP-seq analysis revealed that most TWIST2-mediated gene regulation occurs independent of changes in MYOD binding in FN-RMS cells. Instead, TWIST2 controls the deposition of H3K27 acetylation at distal enhancers by interacting with the chromatin remodelers, SMARCA4 and CHD3, to activate growth-related and repress myogenesis-related TWIST2 target genes. Our findings provide new insights into the role of TWIST2 in maintaining an undifferentiated and tumorigenic state of FN-RMS and highlight the clinical potential of reversing the TWIST2-regulated phenotype.

2023-03-20 | GSE207167 | GEO

TWIST2-Mediated Chromatin Remodeling Promotes Fusion-Negative Rhabdomyosarcoma [ChIP-seq]

2023-03-20 | GSE207165 | GEO

TWIST2-Mediated Chromatin Remodeling Promotes Fusion-Negative Rhabdomyosarcoma [RNA-seq Xenograft]

2023-03-20 | GSE207168 | GEO