YBX1 promotes homologous recombination and resistance to platinum-induced stress in ovarian cancer by recognizing m5C modification
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Wenjun Cheng
PROVIDER: PXD045503 | iProX | Tue Sep 19 00:00:00 BST 2023
REPOSITORIES: iProX
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Project description:Platinum resistance is a clinical challenge in ovarian cancer. Platinating agents induce DNA damage which activate Mre11 nuclease directed DNA damage signalling and response (DDR). Upregulation of DDR may promote chemotherapy resistance. Here we have comprehensively evaluated Mre11 in epithelial ovarian cancers. In clinical cohort that received platinum- based chemotherapy (n=331), Mre11 protein overexpression was associated with aggressive phenotype and poor progression free survival (PFS) (p=0.002). In the ovarian cancer genome atlas (TCGA) cohort (n=498), Mre11 gene amplification was observed in a subset of serous tumours (5%) which correlated highly with Mre11 mRNA levels (p<0.0001). Altered Mre11 levels was linked with genome wide alterations that can influence platinum sensitivity. At the transcriptomic level (n=1259), Mre11 overexpression was associated with poor PFS (p=0.003). ROC analysis showed an area under the curve (AUC) of 0.642 for response to platinum-based chemotherapy. Pre-clinically, Mre11 depletion by gene knock down or blockade by small molecule inhibitor (Mirin) reversed platinum resistance in ovarian cancer cells and in 3D spheroid models. Importantly, Mre11 inhibition was synthetically lethal in platinum sensitive XRCC1 deficient ovarian cancer cells and 3D-spheroids. Selective cytotoxicity was associated with DNA double strand break (DSB) accumulation, S-phase cell cycle arrest and increased apoptosis. We conclude that pharmaceutical development of Mre11 inhibitors is a viable clinical strategy for platinum sensitization and synthetic lethality in ovarian cancer.
2022-07-04 | GSE160540 | GEO
Project description:Platinum resistance is a clinical challenge in ovarian cancer. Platinating agents induce DNA damage which activate Mre11 nuclease directed DNA damage signalling and response (DDR). Upregulation of DDR may promote chemotherapy resistance. Here we have comprehensively evaluated Mre11 in epithelial ovarian cancers. In clinical cohort that received platinum- based chemotherapy (n=331), Mre11 protein overexpression was associated with aggressive phenotype and poor progression free survival (PFS) (p=0.002). In the ovarian cancer genome atlas (TCGA) cohort (n=498), Mre11 gene amplification was observed in a subset of serous tumours (5%) which correlated highly with Mre11 mRNA levels (p<0.0001). Altered Mre11 levels was linked with genome wide alterations that can influence platinum sensitivity. At the transcriptomic level (n=1259), Mre11 overexpression was associated with poor PFS (p=0.003). ROC analysis showed an area under the curve (AUC) of 0.642 for response to platinum-based chemotherapy. Pre-clinically, Mre11 depletion by gene knock down or blockade by small molecule inhibitor (Mirin) reversed platinum resistance in ovarian cancer cells and in 3D spheroid models. Importantly, Mre11 inhibition was synthetically lethal in platinum sensitive XRCC1 deficient ovarian cancer cells and 3D-spheroids. Selective cytotoxicity was associated with DNA double strand break (DSB) accumulation, S-phase cell cycle arrest and increased apoptosis. We conclude that pharmaceutical development of Mre11 inhibitors is a viable clinical strategy for platinum sensitization and synthetic lethality in ovarian cancer.
2022-07-04 | GSE198648 | GEO
Project description:Aims: Deubiquitinases (DUBs) are proteases with emerging roles in cancer progression and therapy resistance, yet their contribution to drug resistance in ovarian cancer remains underexplored. Ovarian cancer patients often fail to benefit from platinum-based therapy, highlighting the need to identify novel factors involved in drug resistance. To this end we performed a CRISPR/Cas9 screen targeting DUB family to identify genes essential for platinum- resistant ovarian carcinoma cell survival. Methods: A CRISPR/CAS9 DUB knockout screen was performed on IGROV-1 parental and platinum-resistant ovarian carcinoma cells. Preclinical pharmacology approaches were also applied. Results: We identified USP18 as a survival factor in platinum-resistant ovarian cancer cells. USP18 expression was elevated at the mRNA and protein levels across five platinum-resistant cell lines. Knockdown and CRISPR/CAS9 editing of USP18 sensitized cells to cisplatin, coinciding with impaired repair of cisplatin-induced DNA damage. RNA-seq of USP18 RNA interfered and edited cells revealed the modulation of pathways including DNA repair. A peptide-based USP18 inhibitor suppressed growth of resistant cells, supporting its role in sustaining the growth of platinum-resistant cells. Conclusion: We identified USP18 as a novel mediator of platinum resistance in ovarian cancer, through modulating DNA repair. Targeting USP18 may offer a therapeutic strategy to improve outcomes in platinum-resistant ovarian cancer.
2026-05-29 | GSE326132 | GEO
Project description:Platinum resistance is a major drawback in the treatment of ovarian cancer. Evidence suggests that microRNAs are key players in the initiation, progression, and drug resistance of cancer cells. However, the precise miRNAs dysregulated and contributing to platinum resistance in ovarian cancer cells have not been fully elucidated. Here, we conducted a miRNA expression profiling of cisplatin-sensitive (A2780) and cisplatin-resistant (CP20 and CIS) ovarian cancer cells to identify potential miRNAs involved in platinum resistance.
2020-11-20 | GSE161784 | GEO
Project description:Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Most TNBCs are initially sensitive to DNA damaging chemotherapy, a substantial fraction acquire resistance to treatments and progress to advanced stages associated with poor prognosis. We identify the spliceosome U2 small nuclear ribonucleoprotein (snRNP) complex as a modulator of chemotherapy efficacy in TNBC. Transient treatment with U2snRNP inhibitors induced a persistent DNA damage in TNBC cells and patient-derived organoids (PDOs), regardless of their homologous recombination proficiency. Transcriptome analyses revealed that U2snRNP inhibition causes a pervasive deregulation of genes involved in the DNA damage response (DDR), which relied on their genomic structure characterized by a high number of small exons. Importantly, a pulse of splicing inhibition was sufficient to elicit long-lasting repression of DDR proteins and to enhance the cytotoxic effect of platinum-based drugs and poly ADP-ribose polymerase inhibitors (PARPi) in multiple TNBC models. These findings identify the U2snRNP as an actionable target that can be exploited to enhance chemotherapy efficacy in TNBCs.
2025-07-04 | GSE271749 | GEO
Project description:Homologous recombination deficiency (HRD) has emerged as a key vulnerability in selected cancer types and is associated with response to platinum and PARPi-based treatment strategies. However, additional biomarkers and targeted therapy options are needed to broaden the range of patients that could benefit from this therapeutic niche. Here, we show that the SARC-HRD signature, composed of ten genes of the homologous recombination repair pathway, stratifies a cohort of sarcoma patients, and associates with genomic biomarkers of HRD, with disease progression and with the CINSARC prognostic signature. Equivalently to CINSARC, high levels of SARC-HRD are associated with poor metastasis-free survival, underscoring the potential of SARC-HRD to predict disease outcome. By pharmacotyping patient-derived cell models, we identified promising drug targets within the DNA damage response for sarcoma with HRD traits. Inhibition of ATR, CHK1 and WEE1 elicited synthetic lethality in sarcoma cells with HRD, which concomitantly showed an upregulation of ATR signaling. Combinatorial drug testing further revealed synergistic drug combinations between ATRi, WEE1i, PARP1/2i and chemotherapeutic agents with potential clinical impact. Mechanistically, targeting ATR signaling at multiple levels induced a replication defect and apoptotic cell death. Taken together, our results demonstrate the therapeutic benefit of targeting DDR mechanisms in sarcoma with HRDness traits and their potential clinical utility for treating a broader spectrum of tumor types.
2026-06-04 | GSE299349 | GEO
Project description:Cisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer. However, resistance to these platinum-based drugs occurs in the large majority of initially responsive tumors, subsequently resulting in a poor long-term prognosis. To model the onset of drug resistance, we measured gene expression alterations associated with cisplatin resistance. We treated clonally derived, drug-sensitive A2780 epithelial ovarian cancer cells with increasing concentrations of cisplatin. After 5 cycles of drug selection, the isogenic drug-sensitive (parental A2780) and -resistant (Round5 A2780) cell lines were subjected to mRNA expression microarray analyses.
2009-04-17 | E-GEOD-15372 | biostudies-arrayexpress
Project description:Resistance to platinum compounds represents a major obstacle to the cure of ovarian carcinoma. The molecular profiling of drug-sensitive and drug-resistant cells may be helpful to clarify if altered gene expression can contribute to the drug-resistant phenotype. The expression pattern of three ovarian carcinoma cell lines was examined. The analysis revealed the modulation of several genes in the two platinum-resistant cell lines as compared to parental platinum-sensitive cells. The integration of the information obtained through gene expression analysis may be useful to clarify the specific molecular alterations of factors and pathway favouring survival of tumor cells.
2018-06-26 | GSE58470 | GEO
Project description:Cisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer. However, resistance to these platinum-based drugs occurs in the large majority of initially responsive tumors, subsequently resulting in a poor long-term prognosis. To model the onset of drug resistance, and investigate the DNA methylation alterations associated with cisplatin resistance, we treated clonally derived, drug-sensitive A2780 epithelial ovarian cancer cells with increasing concentrations of cisplatin. After several cycles of drug selection, the isogenic drug-sensitive and -resistant pairs were subjected to global CGI methylation microarray analyses. We treated clonally derived, drug-sensitive A2780 epithelial ovarian cancer cells with increasing concentrations of cisplatin. After several cycles of drug selection, the isogenic drug-sensitive and -resistant pairs were subjected to global CGI methylation analyses by differential methylation hybridization (DMH) using a customed 44K promoter CGI microarray.
2010-06-19 | E-GEOD-15373 | biostudies-arrayexpress
Project description:Chemo-resistance to platinum such as cisplatin is critical in the treatment of ovarian cancer. Recent evidences have linked epithelial-mesenchymal transition (EMT) with the drug resistance as a contributing mechanism. The current study explored the connection between cellular responses to cisplatin with EMT in ovarian cancer. 46 ovarian carcinoma cell lines expression data with and without Cisplatin treatment.
2014-07-29 | E-GEOD-47856 | biostudies-arrayexpress