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

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

PROVIDER: PRJNA1138761 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29920086_1.fastq.gz	Fastqsanger.gz
	SRR29920086_2.fastq.gz	Fastqsanger.gz
	SRR29920087_1.fastq.gz	Fastqsanger.gz
	SRR29920087_2.fastq.gz	Fastqsanger.gz
	SRR29920088_1.fastq.gz	Fastqsanger.gz

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

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 | GSE272802 | GEO

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

2025-02-10 | GSE273102 | GEO

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

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

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Antagonizing functions of SPOP and ERG Drive Incompatible Subtypes of Prostate Cancer

Project description:Bernasocchi T, El Tekle G, Bolis M, Svinkina T, Zoma M, Rinaldi A, Ceserani V, Janouskova H, Schram P, Carbone G, Alimonti A, Moch H, Carr SA, Udeshi ND, Theurillat JP. 2018. While the co-operation of cancer driver genes in tumorigenesis has been studied, 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. Nevertheless, the underlying basis of this observation is poorly understood. Here, we show that ERG and mutant SPOP, even though oncogenic on their own, are together synthetic sick. At the molecular level, both driver genes inhibit each other in a reciprocal manner. In ERG-driven tumors, wild type SPOP is required to dampen androgen receptor (AR) signaling and sustain ERG activity in part through its ability to degrade the bromodomain histone reader ZMYND11. Consequently, loss-of-function mutations in SPOP unleash excessive AR signaling and reduce ERG function. Conversely, oncogenic androgen receptor signaling driven by mutant SPOP is repressed by ERG. The incompatibility of mutant SPOP and ERG may help to understand why SPOP mutant tumors frequently harbor gene deletions in the chromatin-modifying enzyme CHD1. We find that mutant SPOP promotes the generation of ERG rearrangements in a CHD1-dependent manner. Thus, CHD1 gene deletions may protect SPOP-mutant tumors from ERG-mediated growth inhibition. Taken together, our findings reveal the existence of divergent and incompatible paths towards prostate cancer that converge on SPOP function.

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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

CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair

Project description:BACKGROUND: Deletion of the chromatin remodeler CHD1 is a common genomic alteration found in human prostate cancers (PCas). CHD1 loss represents a distinct PCa subtype characterized by SPOP mutation and higher genomic instability [1-3]. However, the role of CHD1 in PCa development in vivo and its clinical utility remain unclear. DESIGN: To study the role of CHD1 in PCa development and its loss in clinical management, we generated a genetically engineered mouse model with prostate-specific deletion of murine Chd1 as well as isogenic CHD1 WT and homozygous deleted human benign and PCa lines. We also developed patient-derived organoid cultures and screened patients with metastatic PCa for CHD1 loss. RESULTS: We demonstrate that CHD1 loss sensitizes cells to DNA damage and causes a synthetic lethal response to DNA damaging therapy in vivo, ex vivo and in a patient with metastatic PCa. Mechanistically, CHD1 loss leads to decreased error-free homologous recombination (HR) repair, which is compensated by increased error-prone non-homologous end joining (NHEJ) repair for DNA double-strand break (DSB) repair. CONCLUSIONS: Our study provides the first in vivo and in patient evidence supporting the role of CHD1 in DSB repair and in response to DNA damaging therapy. We uncover mechanistic insights that CHD1 modulates the choice between HR and NHEJ and suggest that CHD1 loss may contribute to genomic instability seen in this subset of PCa patients.

2017-07-26 | GSE84610 | GEO

Effects of Intestine-specifc SREBP2 overactivation on gene expression in mouse jejnum

Project description:The active form of the SREBP2 transcription factor was specifically overexpressed in the intesitne. This was achieved by generating transgenic mouse model (designated as ISR2) in which the transgene represents the N-terminal active SREBP2 transcription factor driven by the villin promoter. In this project, we investigated the effects of overactivation of SREBP2 on gene expression in mouse jejunum Gene expression profile in the jejunum of ISR2 was compared to gene expression profile in the jejunum of their wild type littermates.

2013-10-26 | E-GEOD-51736 | biostudies-arrayexpress

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

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

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

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