Effects of SPOP on gene expression in prostate cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE59432 | GEO | 2014/10/10
SECONDARY ACCESSION(S): PRJNA255304
REPOSITORIES: GEO
Similar Datasets
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: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:Purpose: Little is known about the interplay of driver mutations that never co-occur within the same cancer cells. The latter scenario has been identified in prostate cancer where recurrent gene fusions involving the oncogenic ERG transcription factor and point mutations in the ubiquitin ligase adaptor SPOP are strictly mutually exclusive. We show that ERG and mutant SPOP – even though oncogenic on their own – are together synthetic sick. Description: RNA-Seq of lentiviral-transduced VCaP cells with stable knockdown of wild type SPOP (2 x hairpins) or stable overexpression of either wild-type or mutant SPOP (Y87C, F102C, W131G).
2020-12-05 | E-MTAB-7165 | biostudies-arrayexpress
Project description:Purpose: Little is known about the interplay of driver mutations that never co-occur within the same cancer cells. The latter scenario has been identified in prostate cancer where recurrent gene fusions involving the oncogenic ERG transcription factor and point mutations in the ubiquitin ligase adaptor SPOP are strictly mutually exclusive. We show that ERG and mutant SPOP – even though oncogenic on their own – are together synthetic sick. Description: LNCaP cells in presence/absence of stable ΔERG overexpression, were infected with lentivirus to overexpress either wild-type or mutant SPOP (Y87C, F102C, W131G, F133S).
2020-12-10 | E-MTAB-7170 | biostudies-arrayexpress
Project description:Abnormal DNA methylation is one of the major factors driving oncogenesis and therapy resistance in cancer. The CULLIN3-RBX1 E3 ubiquitin ligase adaptor gene SPOP is the most frequently mutated gene in primary prostate cancers (PCa). SPOP-mutated prostate tumors strikingly associate with strongly elevated levels of genome-wide DNA hypermethylation, although the underlying mechanism remains elusive.We use Illumina Infinium MethylationEPIC BeadChip to depict DNA methylation in control and SPOP F102C stabily expressed 22Rv1 cells. Genomic DNA of cells are extracted and quantified by PicoGreen, followed by Illumina Infinium arrays. We find that SPOP mutant expression increases not only the overall cellular level of DNA methylation, but also specifically at loci of a subset of tumor suppressor genes (TSG) including FOXO3 and NDRG1, and this effect is mediated by GLP/G9a binding with DNMT proteins.These findings reveal a previously uncharacterized mechanism by which SPOP mutations promote DNA hypermethylation through stabilization GLP as a chromatin recruiter of DNMT. Our results also suggest that targeting DNA hypermethylation is a viable strategy for effective management of SPOP mutated PCa.
2021-08-01 | GSE179234 | GEO
Project description:Abnormal DNA methylation is one of the major factors driving oncogenesis and therapy resistance in cancer. The CULLIN3-RBX1 E3 ubiquitin ligase adaptor gene SPOP is the most frequently mutated gene in primary prostate cancers (PCa). SPOP-mutated prostate tumors strikingly associate with strongly elevated levels of genome-wide DNA hypermethylation, although the underlying mechanism remains elusive. We use reduced representation bisulfite sequencing (RRBS) to depict DNA methylation in control and SPOP F133V stably expressed 22Rv1 cells. Genomic DNA of cells are extracted and treated with restriction enzyme and followed by bisulfite sequencing to enrich for areas of the genome with a high CpG content. We find that SPOP mutant expression increases not only the overall cellular level of DNA methylation, but also specifically at loci of a subset of tumor suppressor genes (TSG) including FOXO3 and NDRG1, and this effect is mediated by GLP/G9a binding with DNMT proteins. These findings reveal a previously uncharacterized mechanism by which SPOP mutations promote DNA hypermethylation through stabilization GLP as a chromatin recruiter of DNMT. Our results also suggest that targeting DNA hypermethylation is a viable strategy for effective management of SPOP mutated PCa.
2021-08-01 | GSE155491 | GEO
Project description:SPOP is one of the most frequent mutated genes in prostate cancer. In the current study, we identified CCNE1 as its substrate. SPOP directly interacts with CCNE1, poly-ubiquitinates CCNE1 in vivo and in vitro, and represses cancer-related phenotypes induced by CCNE1 expression. Thus, we reveal a new mechanism for SPOP in repressing prostate cancer tumorigenesis.
2018-10-03 | GSE100743 | 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