Oncogenic RAD21 Amplification Coordinates with YAP/TEAD Transcriptional Co-Repressor Complex to Drive Tumorigenesis in High Grade Serous Ovarian Cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA659364 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12515038.fastq.gz | Fastqsanger.gz | |||
| SRR12515039.fastq.gz | Fastqsanger.gz | |||
| SRR12515040.fastq.gz | Fastqsanger.gz | |||
| SRR12515041.fastq.gz | Fastqsanger.gz | |||
| SRR12515042.fastq.gz | Fastqsanger.gz |
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Project description:Ovarian cancer (OV) is the leading cause of mortality from gynaecological malignancies with poor prognosis and limited therapeutic options. Prevalent copy number alteration (CNA) is a genetic characteristic of OV, but its contribution to tumorigenesis remain unclear. Here, we identify RAD21, a component of the cohesin complex, as a frequently amplified and overexpressed oncogene in high grade serous ovarian cancer (HGSOC), the most common subtype of OV. RAD21 copy number amplification and overexpression are correlated with poor prognosis in HGSOC. In HGSOC cells and xenograft models, depletion of RAD21 inhibited cell proliferation by inducing mitotic phase arrest and thereby reducing tumour growth, whereas overexpression of RAD21 conferred resistance to carboplatin. Mechanistically, we found that RAD21 interacts with YAP/TEAD4 transcriptional co-repressors and recruits NuRD complex to suppress the downstream targets. Additionally, genetic and pharmacologic inhibition of YAP disrupts the co-repressor complex to suppress the oncogenic activity of RAD21 and recapitulates the phenotypes of RAD21 depletion in HGSOC. Therefore, our work sheds light on the oncogenic role of frequent CNAs and identifies a previously unrecognized role of RAD21/YAP complex which contributes to tumorigenesis and chemo-resistance in HGSOC.
2023-04-10 | GSE156845 | GEO
Project description:Ovarian cancer (OV) is the leading cause of mortality from gynaecological malignancies with poor prognosis and limited therapeutic options. Prevalent copy number alteration (CNA) is a genetic characteristic of OV, but its contribution to tumorigenesis remain unclear. Here, we identify RAD21, a component of the cohesin complex, as a frequently amplified and overexpressed oncogene in high grade serous ovarian cancer (HGSOC), the most common subtype of OV. RAD21 copy number amplification and overexpression are correlated with poor prognosis in HGSOC. In HGSOC cells and xenograft models, depletion of RAD21 inhibited cell proliferation by inducing mitotic phase arrest and thereby reducing tumour growth, whereas overexpression of RAD21 conferred resistance to carboplatin. Mechanistically, we found that RAD21 interacts with YAP/TEAD4 transcriptional co-repressors and recruits NuRD complex to suppress the downstream targets. Additionally, genetic and pharmacologic inhibition of YAP disrupts the co-repressor complex to suppress the oncogenic activity of RAD21 and recapitulates the phenotypes of RAD21 depletion in HGSOC. Therefore, our work sheds light on the oncogenic role of frequent CNAs and identifies a previously unrecognized role of RAD21/YAP complex which contributes to tumorigenesis and chemo-resistance in HGSOC.
2023-04-10 | GSE193620 | GEO
Project description:TEAD transcription factors are responsible for the transcriptional output of Hippo signalling1,2. TEAD activity is primarily regulated by phosphorylation of its coactivators YAP and TAZ3,4. In addition, cysteine palmitoylation has recently been shown to regulate TEAD activity5,6. Here, we report lysine long-chain fatty acylation as a novel posttranslational modification of TEADs. Lysine fatty acylation occurs spontaneously via intramolecular transfer of acyl groups from the proximal acylated cysteine residue. Lysine fatty acylation, like cysteine palmitoylation, contributes to the transcriptional activity of TEADs by enhancing the interaction with YAP and TAZ, but it is more stable than cysteine acylation, suggesting that the lysine fatty-acylated TEAD acts as a “stable active form”. Significantly, lysine fatty acylation of TEAD increased upon Hippo signalling activation, despite a decrease in cysteine acylation. Our results provide new insight into the role of fatty acyl modifications in the regulation of TEAD activity.
2023-03-19 | PXD033939 | Pride
Project description:MTD project_description Inflammation and decreased stem cell function characterize organism aging, yet the relationship between these factors remains incompletely understood. This study shows that aged hematopoietic stem and progenitor cells exhibit increased ground-stage NF-κB activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-κB signals, by increasing chromatin accessibility of inter-/intra-genic and enhancer regions. Rad21/NF-κB are required for normal differentiation, but limit self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-κB dependent manner. HSCs from aged mice fail to downregulate Rad21/cohesin and inflammation/differentiation inducing signals in the resolution phase after acute inflammation. and The inhibition of cohesin/NF-κB is sufficient to revert the hypersensitivity of aged HSPCs to inflammation-induced differentiation. During aging, myeloid-biased HSCs with disrupted and naturally occurring reduced expression of Rad21/cohesin are increasingly selected over lymphoid-biased HSCs. Together, Rad21/cohesin mediated NF-κB signaling limits HSPC function during aging and selects for cohesin deficient HSCs with myeloid skewed differentiation.
2018-11-28 | PXD011537 | Pride
Project description:We recently identified recurrent mutations of cohesin complex in myeloid neoplasms through whole-exome sequencing analysis. RAD21 is one of the main components of the cohesin complex. In this study, to investigate the biological impact of wild-type RAD21 on Kasumi1 cells harboring RAD21 mutation, Kasumi1 cells were retrovirally transduced with either mock or wild-type RAD21, and expression array was performed. Expression analysis was performed for mock- or wild-type RAD21-transduced Kasumi-1 cells in triplicate. The experiment was performed twice independently.
2013-07-16 | E-GEOD-47641 | biostudies-arrayexpress
Project description:TEAD1 emerged as an estrogen-sensitive gene that was upregulated in a HFD mouse model and in NAFLD patients. We investigated the roles of TEAD in NAFLD by treating primary human hepatocyte spheroids with two small molecule inhibitors blocking the TEAD/YAP interaction. One small molecule blocks the interaction by inhibiting TEAD autopalmitoylation (TEADap), the second small molecule blocks the interaction by binding to the surface of the TEAD protein (TEADsf).
2024-02-22 | E-MTAB-13207 | biostudies-arrayexpress
Project description:The Cohesin complex has recently been described to regulate gene expression. We wanted to determine the gene expression profile specific in mouse ES cells after depletion of the Cohesin subunit Rad21. We used microarrays to detail the global programme of gene expression underlying depletion of Rad21 and identified distinct early development related genes up-regulated and many pluripotency related genes downregulated. Rad21 was depleted in R1/E ES cells for 48h using esiRNAs against Rad21. An esiRNA against non-targeting Luciferase was used as a negative control
2011-05-19 | E-GEOD-23923 | biostudies-arrayexpress
Project description:RAD21 plays multi-functional roles in cell. We explored which genes are target of RAD21 in the cell. We used microarray to find out the target of RAD21 comparing between shGFP(control) and shRAD21 expressing MCF7 cells.
2016-06-01 | GSE82049 | GEO
Project description:RAD21 plays multi-functional roles in cell. We explored which genes are target of RAD21 in the cell. We used microarray to find out the target of RAD21 comparing between shGFP(control) and shRAD21 expressing MCF7 cells. we stably expressed shGFP or shRAD21 in each MCF7 cell and selected single cells having high transfection efficiency of shRNAs. And then we had cultured the single cells for 30 days to harvest sufficient cells.
2016-06-01 | E-GEOD-82049 | biostudies-arrayexpress
Project description:TEAD transcription factors (TEAD1-4) serve as the primary effectors of the Hippo signaling pathway in various cancers. There has been significant progress in the development of therapeutic strategies aimed at disrupting the interaction of TEAD with its coactivators YAP/TAZ. However, targeted therapy leads to the emergence of resistance which poses a barrier to achieving complete cures. Currently, the underlying mechanism of resistance to TEAD inhibition in cancers remains unexplored. We uncover that upregulation of the AP-1 transcription factors, along with restored YAP/TEAD activity, drives resistance to GNE-7883, a pan-TEAD and allosteric TEAD inhibitor. Acute GNE-7883 treatment abrogates YAP binding and attenuates FOSL1 activity but compensation by increased MAPK pathway activity remains insufficient for cell survival. In contrast, TEAD inhibitor resistant cells are able to restore YAP and TEAD occupancy and acquire additional FOSL1 binding sites, leading to increased chromatin accessibility at AP-1 motifs. Resistant cells undergo transcriptional reprogramming to acquire a mesenchymal-like cell state and sustained MAPK activity. We uncover a dependence on the MAPK pathway in the TEAD inhibitor resistant cells, further highlighting the key role of MAPK pathway inhibitors, such as Cobimetinib and Belvarafenib to mitigate resistance mechanisms to TEAD inhibition in Hippo pathway dependent cancers. This study describes a clinically relevant interplay between the Hippo and MAPK pathway in cancers and offers a promising avenue to address TEAD inhibitor resistance in the clinic.
2024-12-17 | GSE273358 | GEO