Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Increased translation driven by a non-canonical EZH2 cistrome creates a synthetic vulnerability in enzalutamide-resistant prostate cancer (CUT&RUN) II

ABSTRACT: Resistance to therapy is a major challenge in castration-resistant prostate cancer (CRPC). Lineage plasticity towards a neuroendocrine phenotype enables CRPC to adapt and survive targeted-therapies. However, the molecular mechanisms of epigenetic reprogramming during this process are still poorly understood. Here we show that the protein kinase PKCl/i phosphorylates the epigenetic regulator enhancer of zeste homologue 2 (EZH2) to regulate its proteasomal degradation and maintain EZH2 as part of the canonical polycomb repressive complex (PRC2). Loss of PKCl/i promotes a switch during enzalutamide treatment to a non-canonical EZH2 cistrome that triggers the transcriptional activation of the translational machinery to induce a transforming growth factor b (TGFb) resistance program. The increased reliance on protein synthesis creates a synthetic vulnerability in PKCl/i-deficient CRPC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272471 | GEO | 2024/10/22

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Increased translation driven by a non-canonical EZH2 cistrome creates a synthetic vulnerability in enzalutamide-resistant prostate cancer (CUT&RUN)

Project description:Resistance to therapy is a major challenge in castration-resistant prostate cancer (CRPC). Lineage plasticity towards a neuroendocrine phenotype enables CRPC to adapt and survive targeted-therapies. However, the molecular mechanisms of epigenetic reprogramming during this process are still poorly understood. Here we show that the protein kinase PKCl/i phosphorylates the epigenetic regulator enhancer of zeste homologue 2 (EZH2) to regulate its proteasomal degradation and maintain EZH2 as part of the canonical polycomb repressive complex (PRC2). Loss of PKCl/i promotes a switch during enzalutamide treatment to a non-canonical EZH2 cistrome that triggers the transcriptional activation of the translational machinery to induce a transforming growth factor b (TGFb) resistance program. The increased reliance on protein synthesis creates a synthetic vulnerability in PKCl/i-deficient CRPC.

2024-10-22 | GSE266949 | GEO

Increased translation driven by a non-canonical EZH2 cistrome creates a synthetic vulnerability in enzalutamide-resistant prostate cancer (scRNA-Seq)

2024-10-22 | GSE266955 | GEO

Increased translation driven by a non-canonical EZH2 cistrome creates a synthetic vulnerability in enzalutamide-resistant prostate cancer (RNA-Seq organoids)

2024-10-22 | GSE266951 | GEO

Increased translation driven by a non-canonical EZH2 cistrome creates a synthetic vulnerability in enzalutamide-resistant prostate cancer (RNA-Seq LNCaP)

2024-10-22 | GSE266950 | GEO

Increased translation driven by a non-canonical EZH2 cistrome creates a synthetic vulnerability in enzalutamide-resistant prostate cancer (RNA-Seq polysome)

2024-10-22 | GSE266954 | GEO

DiazMeco_Increased translation driven by a non-canonical EZH2 cistrome creates a synthetic vulnerability in enzalutamide-resistant prostate cancer_set2

Project description:Identification of phosphopeptides in EZH2 upon PRKCI treatment (kinase). In vitro kinase reactions were performed in buffer containing 25 mM HEPES, 15 mM MgCl2, and 1mM DTT. Two samples were sent to the facility for analysis, EZH2, and EZH2+PRKCI.

2024-05-07 | MSV000094705 | MassIVE

DiazMeco_Increased translation driven by a non-canonical EZH2 cistrome creates a synthetic vulnerability in enzalutamide-resistant prostate cancer_set3

Project description:Identification of phosphopeptides EZH2 in control and kinase-deficient cells. The HA-EZH2 plasmid was transfected in HEK 293T cells, and HA-EZH2 was subsequently purified using HA peptide. The elution was performed with 1mg/mL HA-peptide in Tris buffered saline (TBS with 150mM NaCl), pH 7.5 in a final volume of 100 microL and a concentration of 150-250 ng/microL. Two samples were sent to the facility for analysis: HEK293T-sgC and sgPRKCI.

2024-05-07 | MSV000094706 | MassIVE

DiazMeco_Increased translation driven by a non-canonical EZH2 cistrome creates a synthetic vulnerability in enzalutamide-resistant prostate cancer_set1

Project description:Identification of interacting partners from immuno-precipitated HA-EZH2 samples. Endogenous Co-IP was performed using 1.5 mg of nuclear lysate with anti-HA antibody after transfecting HEK 293T cells with HA-EZH2 plasmid. Two IP-ed samples were submitted to the core for analysis, HEK293T-sgC and sgPRKCI.

2024-05-07 | MSV000094704 | MassIVE

Identification of Selective SWI/SNF Dependencies in Enzalutamide-Resistant Prostate Cancer

Project description:Enzalutamide (ENZA) is a potent second-generation antiandrogen commonly used to treat hormone-sensitive and castration-resistant prostate cancer (CRPC) patients. While initially effective, the response is only temporary and the disease almost always develops resistance. Given that many ENZA-resistant tumors are not driven by specific somatic mutations, there is increasing evidence that epigenetic factors can cause ENZA resistance. To explore how resistance arises we systematically tested all the epigenetic modifiers in castration-resistant and ENZA-resistant prostate cancer models using a custom epigenetic CRISPR library. From this, we identified and validated numerous epigenetic modifiers that were selectivity essential including SMARCC2, a core component of the SWI/SNF complex (or BAF complex) that regulates gene expression by altering DNA accessibility. Additionally, our data demonstrated canonical BAF complex dependency in ENZA-resistance that was also observed following the loss of DPF2, a canonical BAF-specific component. We showed that the chromatin occupancy of SMARCC2 and BRG1 was expanded in acquired ENZA resistance to the regions that overlap with transcriptional activity and CRPC-associated transcription factors that are significantly accessible in CRPC patients. Overall, our study revealed a regulatory role for SMARCC2 in ENZA-resistant prostate cancer and demonstrated the feasibility of targeting the SWI/SNF complex in late-stage PCa.

2024-12-13 | GSE280839 | GEO