Ontology highlight
ABSTRACT:
PROVIDER: PRJNA357942 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5118390.fastq.gz | Fastqsanger.gz | |||
| SRR5118391.fastq.gz | Fastqsanger.gz | |||
| SRR5118392.fastq.gz | Fastqsanger.gz | |||
| SRR5118393.fastq.gz | Fastqsanger.gz | |||
| SRR5118384.fastq.gz | Fastqsanger.gz |
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Project description:Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising therapeutics of cancers including prostate cancer. The E3 ubiquitin ligase adaptor protein speckle-type POZ protein (SPOP) is implicated in human prostate cancers due to its frequent mutation. Here we demonstrate that SPOP binds to the BET proteins BRD2, BRD3 and BRD4. Wild-type SPOP, but not prostate cancer-associated mutants, promotes polyubiquitination and proteasome degradation of BET proteins by recognizing a common degron motif. BET protein levels are highly elevated in SPOP-mutated prostate cancers in patients. Expression of cancer-derived SPOP mutants upregulates cholesterol biosynthesis genes and confers resistance to the BET inhibitor in cultured prostate cancer cells and tumors in mice, and this effect can be overcome by the AKT inhibitor. Our findings reveal BET proteins as proteolytic targets of SPOP and identify deregulated cholesterol biosynthesis as a downstream event of SPOP mutation-mediated tumorigenesis and therapy resistance in prostate cancer.
2018-03-08 | GSE98010 | GEO
Project description:Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising therapeutics of cancers including prostate cancer. The E3 ubiquitin ligase adaptor protein speckle-type POZ protein (SPOP) is implicated in human prostate cancers due to its frequent mutation. Here we demonstrate that SPOP binds to the BET proteins BRD2, BRD3 and BRD4. Wild-type SPOP, but not prostate cancer-associated mutants, promotes polyubiquitination and proteasome degradation of BET proteins by recognizing a common degron motif. BET protein levels are highly elevated in SPOP-mutated prostate cancers in patients. Expression of cancer-derived SPOP mutants upregulates cholesterol biosynthesis genes and confers resistance to the BET inhibitor in cultured prostate cancer cells and tumors in mice, and this effect can be overcome by the AKT inhibitor. Our findings reveal BET proteins as proteolytic targets of SPOP and identify deregulated cholesterol biosynthesis as a downstream event of SPOP mutation-mediated tumorigenesis and therapy resistance in prostate cancer.
2017-07-24 | GSE88871 | GEO
Project description:Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising therapeutics of cancers including prostate cancer. The E3 ubiquitin ligase adaptor protein speckle-type POZ protein (SPOP) is implicated in human prostate cancers due to its frequent mutation. Here we demonstrate that SPOP binds to the BET proteins BRD2, BRD3 and BRD4. Wild-type SPOP, but not prostate cancer-associated mutants, promotes polyubiquitination and proteasome degradation of BET proteins by recognizing a common degron motif. BET protein levels are highly elevated in SPOP-mutated prostate cancers in patients. Expression of cancer-derived SPOP mutants upregulates cholesterol biosynthesis genes and confers resistance to the BET inhibitor in cultured prostate cancer cells and tumors in mice, and this effect can be overcome by the AKT inhibitor. Our findings reveal BET proteins as proteolytic targets of SPOP and identify deregulated cholesterol biosynthesis as a downstream event of SPOP mutation-mediated tumorigenesis and therapy resistance in prostate cancer.
2017-07-24 | GSE78213 | GEO
Project description:Janouskova H, El Tekle G, Bellini E, Udeshi ND, Rinaldi A, Ulbricht A, Bernasocchi T, Civenni G, Losa M, Svinkina T, Bielski CM, Kryukov GV, Cascione L, Sara Napoli S, Enchev RI, Mutch DG, Carney ME, Berchuck A, Winterhoff BJN, Broaddus RR, Schraml P, Moch H, Bertoni F, Catapano CV, Peter M, Carr SA, Garraway LA, Wild PJ, and Theurillat JP. Nature Medicine 2017.
It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer-specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition.These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations.
2016-12-16 | MSV000080401 | MassIVE
Project description:SPOP is a ubiquitin ligase adaptor frequently mutated in prostate cancer. It is involved in ubiquitination and degradation of substrate proteins. We examined the impact of wild-type and mutant SPOP on the transcriptional profile of prostate cancer cells. We cloned several naturally occurring (in human prostate cancer) SPOP mutants and expressed the corresponding constructs in prostate cancer cells. Our experimental conditions were: Human prostate cancer cells (LNCaP-Abl), transfected with control vector, SPOP-wt, and any of the following mutants: SPOP-F102C, SPOP-F133V, SPOP-F133L (2-4 biological replicates each). We analyzed their gene expression profiles for differences induced by SPOP-wt vs SPOP-mutant.
2014-10-10 | E-GEOD-59432 | biostudies-arrayexpress
Project description:SPOP is known to bind to serine/theronine-rich degrons on substrate proteins. We identified two degron sequences within the PWWP and MYND domain of ZMYND11, a novel SPOP substrate, and investigated whether ZMYND11 may contribute to the transcriptional output of mutant SPOP in VCaP cancer cells. We mapped the genomic occupancy of ZMYND11 in VCaP cells over-expressing either wild type SPOP or the recurrent SPOP-Y87C mutant by ChIPseq. Genomic binding sites in the SPOP-Y87C mutant were increased over wild type SPOP, consistent with the increased ZMYND11 expression levels in the former.
2020-12-05 | E-MTAB-7174 | biostudies-arrayexpress
Project description:SPOP mutation confers intrinsic BET inhibitor resistance in prostate cancer
| PRJNA348842 | ENA
Project description:Speckle-type POZ protein (SPOP), an E3 ubiquitin ligase, acts as a tumor suppressor. We identified G3BP1 as non-substrate interactor of SPOP. G3BP1 is a well-known oncogene in many cancer types, but its role in prostate cancer (PCa) remains largely elusive. We showed that G3BP1 functions as an upstream regulator and potent endogenous inhibitor of Cul3SPOP, suggesting a distinctive Cul3SPOP inactivation independent of SPOP mutations. Transcriptomic analysis together with functional studies revealed that the G3BP1-SPOP ubiquitin signaling axis is involved in PCa progression through activating AR signaling. Further, AR upregulates G3BP1 to potentiate feed-forward amplification of signaling through G3BP1-SPOP axis. Overall, we show G3BP1high PCa tumors constitute a new subset where G3BP1 inhibits Cul3SPOP function to upregulate AR signaling, and promotes tumorigenesis.
2021-09-26 | GSE138612 | GEO
Project description: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.
2021-11-25 | PXD029120 | Pride
Project description:SPOP mutation confers intrinsic BET inhibitor resistance in prostate cancer (BRDs_OE_RNA-seq)
| PRJNA383658 | ENA