Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters











Database
Language
Publication year range
1.
Nat Commun ; 12(1): 6662, 2021 11 18.
Article in English | MEDLINE | ID: mdl-34795264

ABSTRACT

SPOP, an E3 ubiquitin ligase, acts as a prostate-specific tumor suppressor with several key substrates mediating oncogenic function. However, the mechanisms underlying SPOP regulation are largely unknown. Here, we have identified G3BP1 as an interactor of SPOP and functions as a competitive inhibitor of Cul3SPOP, suggesting a distinctive mode of Cul3SPOP inactivation in prostate cancer (PCa). Transcriptomic analysis and functional studies reveal a G3BP1-SPOP ubiquitin signaling axis that promotes PCa progression through activating AR signaling. Moreover, AR directly upregulates G3BP1 transcription to further amplify G3BP1-SPOP signaling in a feed-forward manner. Our study supports a fundamental role of G3BP1 in disabling the tumor suppressive Cul3SPOP, thus defining a PCa cohort independent of SPOP mutation. Therefore, there are significantly more PCa that are defective for SPOP ubiquitin ligase than previously appreciated, and these G3BP1high PCa are more susceptible to AR-targeted therapy.


Subject(s)
Cullin Proteins/antagonists & inhibitors , DNA Helicases/metabolism , Nuclear Proteins/antagonists & inhibitors , Poly-ADP-Ribose Binding Proteins/metabolism , Prostatic Neoplasms/metabolism , RNA Helicases/metabolism , RNA Recognition Motif Proteins/metabolism , Receptors, Androgen/metabolism , Repressor Proteins/antagonists & inhibitors , Androgen Receptor Antagonists/pharmacology , Animals , Carcinogenesis , Cell Line, Tumor , Cell Movement , Cell Survival/drug effects , Cullin Proteins/metabolism , DNA Helicases/genetics , Gene Expression Regulation, Neoplastic , Humans , Male , Mice , Mutation , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Poly-ADP-Ribose Binding Proteins/genetics , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , RNA Helicases/genetics , RNA Recognition Motif Proteins/genetics , Repressor Proteins/genetics , Repressor Proteins/metabolism , Signal Transduction/drug effects , Ubiquitin-Protein Ligases/antagonists & inhibitors , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism
2.
Nat Commun ; 9(1): 2404, 2018 06 19.
Article in English | MEDLINE | ID: mdl-29921838

ABSTRACT

A major hurdle in the study of rare tumors is a lack of existing preclinical models. Neuroendocrine prostate cancer is an uncommon and aggressive histologic variant of prostate cancer that may arise de novo or as a mechanism of treatment resistance in patients with pre-existing castration-resistant prostate cancer. There are few available models to study neuroendocrine prostate cancer. Here, we report the generation and characterization of tumor organoids derived from needle biopsies of metastatic lesions from four patients. We demonstrate genomic, transcriptomic, and epigenomic concordance between organoids and their corresponding patient tumors. We utilize these organoids to understand the biologic role of the epigenetic modifier EZH2 in driving molecular programs associated with neuroendocrine prostate cancer progression. High-throughput organoid drug screening nominated single agents and drug combinations suggesting repurposing opportunities. This proof of principle study represents a strategy for the study of rare cancer phenotypes.


Subject(s)
Neuroendocrine Tumors/genetics , Organoids/metabolism , Prostate/metabolism , Prostatic Neoplasms/genetics , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/genetics , Epigenomics/methods , Gene Expression Profiling/methods , Genomics/methods , Humans , Male , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Neuroendocrine Tumors/drug therapy , Neuroendocrine Tumors/pathology , Organoids/pathology , Phenotype , Prostate/pathology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Xenograft Model Antitumor Assays
SELECTION OF CITATIONS
SEARCH DETAIL