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SPOP mutations derived from prostate cancer establish a DNA hypermethylation epigenome through stabilizing GLP histone methyltransferase [methylation array]

ABSTRACT: SPOP mutations derived from prostate cancer establish a DNA hypermethylation epigenome through stabilizing GLP histone methyltransferase [methylation array]

PROVIDER: PRJNA742773 | ENA |

REPOSITORIES: ENA

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SPOP mutations derived from prostate cancer establish a DNA hypermethylation epigenome through stabilizing GLP histone methyltransferase

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

SPOP mutations derived from prostate cancer establish a DNA hypermethylation epigenome through stabilizing GLP histone methyltransferase [methylation array]

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

SPOP mutations derived from prostate cancer establish a DNA hypermethylation epigenome through stabilizing GLP histone methyltransferase

Project description:SPOP mutations derived from prostate cancer establish a DNA hypermethylation epigenome through stabilizing GLP histone methyltransferase

| PRJNA649940 | ENA

Effects of SPOP on gene expression in prostate cancer

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

SPOP mutation - SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling

Project description:Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe the first mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia, and invasive poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP drove increased proliferation and a transcriptional signature consistent with human prostate cancer. Using these models and human prostate cancer samples, we show that SPOP mutation activates both PI3K/mTOR and androgen receptor (AR) signaling, effectively uncoupling the normal negative feedback between these two pathways. Associated RNA-seq data deposited in GEO: GSE94839.

2017-03-20 | PXD005309 | Pride

Stable over expression of the SPOP-substrate ZMYND11 in VCaP cells

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. Hence, we performed over-expression of degron-deficient ZMYND11 and degron-deficient ZMYND11 with W294A mutation in VCaP cells. While WT ZMYND11 constructs can be robustly over-expressed at the mRNA level, only the degron-deficient variants yielded a robost increase in ZMYND11 protein expression. Degron mutant-induced transcriptional perturbations partially mimicked SPOP mutant-induced gene expression changes, suggesting that ZMYND11 is sufficient to recapitulate certain features of mutant SPOP.

2020-12-16 | E-MTAB-7173 | biostudies-arrayexpress

Gene Expression Profiling of SPOP Knocked Down Cell

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

Identification of ZMYND11 binding sites in VCaP cells with stable overexpression of either mutant (Y87C) or wild-type SPOP.

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

Stable overexpression and knockdown of mutant- or wild type SPOP in VCaP prostate cancer cells

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

SPOP mutation confers intrinsic BET inhibitor resistance in prostate cancer (BRD4_JQ1_RNA-seq)

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

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