Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Divergent Roles of SPOP and CHD1 in ACSL4 Regulation Reveal Context-dependent Vulnerabilities for Targeting Ferroptosis in Prostate Cancer

ABSTRACT: Genetic heterogeneity contributes to the variable therapeutic responses in prostate cancer (PCa). Frequent SPOP mutations and recurrent CHD1 deletions define distinct molecular subtypes of PCa with differential responses to anti-androgen therapy. Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, has emerged as a promising anticancer strategy. Here, we identify SPOP mutations and CHD1 deletion as key genetic determinants of ferroptosis susceptibility in PCa.

ORGANISM(S): Homo sapiens

PROVIDER: GSE317501 | GEO | 2026/04/09

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

Divergent Roles of SPOP and CHD1 in ACSL4 Regulation Reveal Context-dependent Vulnerabilities for Targeting Ferroptosis in Prostate Cancer

Project description:Divergent Roles of SPOP and CHD1 in ACSL4 Regulation Reveal Context-dependent Vulnerabilities for Targeting Ferroptosis in Prostate Cancer

| PRJNA1414277 | ENA

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

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.

| MSV000082915 | MassIVE

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: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

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

TRIM28 protects TRIM24 from SPOP-mediated degradation and promotes prostate cancer progression [microarray]

Project description:In this study, proteomic profiling of TRIM24 interactome in conjunction with shRNA screening of TRIM24 top-interactors nominated that TRIM28 is indispensable for TRIM24 protein stability. We showed that TRIM28 stabilizes TRIM24 against SPOP-mediated ubiquitination and degradation. TRIM28 promotes TRIM24 and AR transcription activity, androgen-dependent and -independent PCa growth. In addition, we demonstrated that TRIM28 level in high in advanced PCa, which drives TRIM24/AR transcription activity in a similar manner to SPOP mutation, which implies that TRIM28 potentially dictates the therapeutic outcome of TRIM24-targeted therapy.

2018-10-05 | GSE108145 | GEO

TRIM28 protects TRIM24 from SPOP-mediated degradation and promotes prostate cancer progression [ChIP-seq]

2018-10-05 | GSE108144 | GEO