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Homo sapiens

ABSTRACT: SPOP mutation confers intrinsic BET inhibitor resistance in prostate cancer (BRDs_OE_RNA-seq)

PROVIDER: PRJNA383658 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5460860.fastq.gz	Fastqsanger.gz
	SRR5460860_1.fastq.gz	Fastqsanger.gz
	SRR5460860_2.fastq.gz	Fastqsanger.gz
	SRR5460861.fastq.gz	Fastqsanger.gz
	SRR5460861_1.fastq.gz	Fastqsanger.gz

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SPOP mutation confers intrinsic BET inhibitor resistance in prostate cancer

Project description:SPOP mutation confers intrinsic BET inhibitor resistance in prostate cancer

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SPOP mutation confers intrinsic BET inhibitor resistance in prostate cancer (ChIP-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 | GSE88871 | GEO

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

2017-07-24 | GSE78213 | GEO

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

2018-03-08 | GSE98010 | GEO

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

Opposing effects of cancer-type-specific SPOP mutations on BET protein degradation and sensitivity to BET inhibitors

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

CHD1 Loss Hijacks SREBP2-mediated Cholesterol Biosynthesis to Fuel SPOP-deficient Prostate Cancer and Confers Resistance to Castration [scRNA-seq]

Project description:Androgen receptor (AR) is an important driver in the disease progression of castration-resistant prostate cancer (CRPC). Speckle-type BTB/POZ protein (SPOP) mutations stabilize AR and frequently co-occur with the loss of chromodomain helicase DNA-binding protein 1 (CHD1). We generated a new genetically engineered mouse model and prostate cancer cells model containing CHD1 deletion and SPOP mutation to study the underlying mechanism. We found CHD1 loss–induced cholesterol production supplies intratumoral androgen biosynthesis and retains AR transcriptional activity in SPOP-mutated prostate tumors, leading to castration resistance.

2025-02-10 | GSE273102 | GEO

CHD1 Loss Hijacks SREBP2-mediated Cholesterol Biosynthesis to Fuel SPOP-deficient Prostate Cancer and Confers Resistance to Castration

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