High PRMT5 levels, maintained by KEAP1 inhibition, drive chemoresistance in ovarian cancer [ChIP-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1189592 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31476638.fastq.gz | Fastqsanger.gz | |||
| SRR31476639.fastq.gz | Fastqsanger.gz | |||
| SRR31476640.fastq.gz | Fastqsanger.gz | |||
| SRR31476641.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 4 of 4 |
Similar Datasets
Project description:Protein arginine methyl transferases (PRMTs) are generally upregulated in cancers. However, the mechanisms leading to this upregulation and its biological consequences are poorly understood. Here, we identify PRMT5, the main symmetric arginine methyl transferase, as a critical driver of chemoresistance in high-grade serous ovarian cancer (HGSOC). Cancer transcriptome analysis shows that HGSOC tumors express the highest levels of PRMT5. Furthermore, PRMT5 levels and its enzymatic activity are further induced in a Platinum (Pt)-resistant state at the protein level. To reveal potential regulators of high PRMT5 protein levels, we optimized intracellular immunostaining conditions and performed an unbiased CRISPR screening to identify regulators of PRMT5 levels in OC cells. These results led to several critical regulators, including KEAP1, a top-scoring negative regulator of PRMT5 protein levels. Our mechanistic studies show that KEAP1 directly interacts with PRMT5, leading to its ubiquitin-dependent degradation under normal physiological conditions. However, Pt-treatment-mediated stress leads to KEAP1 inhibition, resulting in elevated levels of PRMT5, sufficient to confer cells resistant to Pt. At the genomic level, our chromatin immunoprecipitation and sequencing (ChIP) studies show that elevated PRMT5 directly interacts with the promoters of stress response genes and positively regulates their transcription. In line with increased PRMT5 levels in Pt-resistant cells, pharmacological inhibition of PRMT5 selectively renders these cells selectively sensitive to PRMT5 inhibition compared to chemo-naive or normal fallopian epithelial cells. As such, combined PRMT5 inhibition with Pt results in synergistic cellular cytotoxicity in vitro and tumor volume reduction in vivo in otherwise Pt-resistant patient-derived xenograft tumors. Overall, the findings from this study identify PRMT5 as a critical therapeutic target in Pt-resistant HGSOC cells and reveal the molecular mechanisms that lead to high PRMT5 levels in Pt-treated and chemo-resistant tumors.
2025-02-21 | GSE282674 | GEO
Project description:Protein arginine methyl transferases (PRMTs) are generally upregulated in cancers. However, the mechanisms leading to this upregulation and its biological consequences are poorly understood. Here, we identify PRMT5, the main symmetric arginine methyl transferase, as a critical driver of chemoresistance in high-grade serous ovarian cancer (HGSOC). Cancer transcriptome analysis shows that HGSOC tumors express the highest levels of PRMT5. Furthermore, PRMT5 levels and its enzymatic activity are further induced in a Platinum (Pt)-resistant state at the protein level. To reveal potential regulators of high PRMT5 protein levels, we optimized intracellular immunostaining conditions and performed an unbiased CRISPR screening to identify regulators of PRMT5 levels in OC cells. These results led to several critical regulators, including KEAP1, a top-scoring negative regulator of PRMT5 protein levels. Our mechanistic studies show that KEAP1 directly interacts with PRMT5, leading to its ubiquitin-dependent degradation under normal physiological conditions. However, Pt-treatment-mediated stress leads to KEAP1 inhibition, resulting in elevated levels of PRMT5, sufficient to confer cells resistant to Pt. At the genomic level, our chromatin immunoprecipitation and sequencing (ChIP) studies show that elevated PRMT5 directly interacts with the promoters of stress response genes and positively regulates their transcription. In line with increased PRMT5 levels in Pt-resistant cells, pharmacological inhibition of PRMT5 selectively renders these cells selectively sensitive to PRMT5 inhibition compared to chemo-naive or normal fallopian epithelial cells. As such, combined PRMT5 inhibition with Pt results in synergistic cellular cytotoxicity in vitro and tumor volume reduction in vivo in otherwise Pt-resistant patient-derived xenograft tumors. Overall, the findings from this study identify PRMT5 as a critical therapeutic target in Pt-resistant HGSOC cells and reveal the molecular mechanisms that lead to high PRMT5 levels in Pt-treated and chemo-resistant tumors.
2025-02-21 | GSE282677 | GEO
Project description:Protein arginine methyl transferases (PRMTs) are generally upregulated in cancers. However, the mechanisms leading to this upregulation and its biological consequences are poorly understood. Here, we identify PRMT5, the main symmetric arginine methyl transferase, as a critical driver of chemoresistance in high-grade serous ovarian cancer (HGSOC). Cancer transcriptome analysis shows that HGSOC tumors express the highest levels of PRMT5. Furthermore, PRMT5 levels and its enzymatic activity are further induced in a Platinum (Pt)-resistant state at the protein level. To reveal potential regulators of high PRMT5 protein levels, we optimized intracellular immunostaining conditions and performed an unbiased CRISPR screening to identify regulators of PRMT5 levels in OC cells. These results led to several critical regulators, including KEAP1, a top-scoring negative regulator of PRMT5 protein levels. Our mechanistic studies show that KEAP1 directly interacts with PRMT5, leading to its ubiquitin-dependent degradation under normal physiological conditions. However, Pt-treatment-mediated stress leads to KEAP1 inhibition, resulting in elevated levels of PRMT5, sufficient to confer cells resistant to Pt. At the genomic level, our chromatin immunoprecipitation and sequencing (ChIP) studies show that elevated PRMT5 directly interacts with the promoters of stress response genes and positively regulates their transcription. In line with increased PRMT5 levels in Pt-resistant cells, pharmacological inhibition of PRMT5 selectively renders these cells selectively sensitive to PRMT5 inhibition compared to chemo-naive or normal fallopian epithelial cells. As such, combined PRMT5 inhibition with Pt results in synergistic cellular cytotoxicity in vitro and tumor volume reduction in vivo in otherwise Pt-resistant patient-derived xenograft tumors. Overall, the findings from this study identify PRMT5 as a critical therapeutic target in Pt-resistant HGSOC cells and reveal the molecular mechanisms that lead to high PRMT5 levels in Pt-treated and chemo-resistant tumors.
2025-02-21 | GSE282676 | GEO
Project description:Protein arginine methyl transferases (PRMTs) are generally upregulated in cancers. However, the mechanisms leading to this upregulation and its biological consequences are poorly understood. Here, we identify PRMT5, the main symmetric arginine methyl transferase, as a critical driver of chemoresistance in high-grade serous ovarian cancer (HGSOC). Cancer transcriptome analysis shows that HGSOC tumors express the highest levels of PRMT5. Furthermore, PRMT5 levels and its enzymatic activity are further induced in a Platinum (Pt)-resistant state at the protein level. To reveal potential regulators of high PRMT5 protein levels, we optimized intracellular immunostaining conditions and performed an unbiased CRISPR screening to identify regulators of PRMT5 levels in OC cells. These results led to several critical regulators, including KEAP1, a top-scoring negative regulator of PRMT5 protein levels. Our mechanistic studies show that KEAP1 directly interacts with PRMT5, leading to its ubiquitin-dependent degradation under normal physiological conditions. However, Pt-treatment-mediated stress leads to KEAP1 inhibition, resulting in elevated levels of PRMT5, sufficient to confer cells resistant to Pt. At the genomic level, our chromatin immunoprecipitation and sequencing (ChIP) studies show that elevated PRMT5 directly interacts with the promoters of stress response genes and positively regulates their transcription. In line with increased PRMT5 levels in Pt-resistant cells, pharmacological inhibition of PRMT5 selectively renders these cells selectively sensitive to PRMT5 inhibition compared to chemo-naive or normal fallopian epithelial cells. As such, combined PRMT5 inhibition with Pt results in synergistic cellular cytotoxicity in vitro and tumor volume reduction in vivo in otherwise Pt-resistant patient-derived xenograft tumors. Overall, the findings from this study identify PRMT5 as a critical therapeutic target in Pt-resistant HGSOC cells and reveal the molecular mechanisms that lead to high PRMT5 levels in Pt-treated and chemo-resistant tumors.
2025-02-21 | GSE282675 | GEO
Project description:High PRMT5 levels, maintained by KEAP1 inhibition, drive chemoresistance in ovarian cancer [RNA-seq]
| PRJNA1189593 | ENA
Project description:High PRMT5 levels, maintained by KEAP1 inhibition, drive chemoresistance in ovarian cancer [CRISPR screen]
| PRJNA1189595 | ENA
Project description:High PRMT5 levels, maintained by KEAP1 inhibition, drive chemoresistance in ovarian cancer [ATAC-seq]
| PRJNA1189594 | ENA
Project description:Protein arginine methyl transferases (PRMTs) are generally upregulated in cancers. However, the mechanisms leading to this upregulation and its biological consequences are poorly understood. Here, we identify PRMT5, the main symmetric arginine methyltransferase, as a critical driver of chemoresistance in high-grade serous ovarian cancer (HGSOC). PRMT5 levels and its enzymatic activity are induced in a platinum-resistant (Pt-resistant) state at the protein level. To reveal potential regulators of high PRMT5 protein levels, we optimized intracellular immunostaining conditions and performed unbiased CRISPR screening. We identified Kelch-like ECH-associated protein 1 (KEAP1) as a top-scoring negative regulator of PRMT5. Our mechanistic studies show that KEAP1 directly interacted with PRMT5, leading to its ubiquitin-dependent degradation under normal physiological conditions. At the genomic level, ChIP studies showed that elevated PRMT5 directly interacted with the promoters of stress response genes and positively regulated their transcription. Combined PRMT5 inhibition with Pt resulted in synergistic cellular cytotoxicity in vitro and reduced tumor growth in vivo in Pt-resistant patient-derived xenograft tumors. Overall, the findings from this study identify PRMT5 as a critical therapeutic target in Pt-resistant HGSOC cells and reveal the molecular mechanisms that lead to high PRMT5 levels in Pt-treated and chemo-resistant tumors.
| S-EPMC11910213 | biostudies-literature
Project description:Breast cancer stem cells (BCSCs) are a rare cell population that are responsible for tumour initiation, metastasis, chemoresistance and tumour relapse. Despite this, the mechanism by which BCSCs withstand genotoxic stress is largely unknown. Here, we uncover a pivotal role for the arginine methyltransferase PRMT5 in mediating BCSC chemoresistance by modulation of DNA repair efficiency. Notably, PRMT5 inhibitors synergise with cisplatin and radiotherapy, inducing defective DNA repair thereby potentiating BCSC apoptosis. Mechanistically, we demonstrate the crucial function of PRMT5 in ensuring splicing fidelity of DNA damage response genes, particularly those integral to the Fanconi Anaemia and homologous recombination pathways. A comparison of BCSCs and their bulk cell progeny identified shared (ATM, DDX11, EXO1, FAN1, SLX4) and unique (ATR, RAD17, RAD51D, RUVBL1) PRMT5-dependent alternative splicing events. Surprisingly, these events rarely repressed gene expression, suggesting that PRMT5 inhibition predominantly results in nuclear detention of intron-containing transcripts and the production of non-canonical isoforms with compromised protein function. This study thus reveals promising strategies to improve the therapeutic efficacy of PRMT5 inhibitors that promote effective BCSC eradication.
2024-12-19 | GSE261017 | GEO
Project description:Small cell lung cancer (SCLC) is characterized by exquisite chemosensitivity followed by rapid emergence of chemoresistance. To identify genetic events that drive resistance to cisplatin-etoposide chemotherapy, we conducted cDNA overexpression and CRISPR knockout screens in an in vivo platform centered on chemosensitive patient derived xenograft (PDX) models of SCLC. cDNA overexpression screens revealed MYC, MYCN and MYCL as drivers of tumor cell growth through chemotherapy. CRISPR knockout screens identified the KEAP1/NRF2 pathway and members of the SAGA (Spt-Ada-Gcn5 acetyltransferase) complex, including the deubiquitylase USP22. We demonstrated that knockout of either KEAP1 or USP22 switches chemosensitive PDX models to become chemoresistant, with our data supporting distinct molecular consequences of each, including suppression of DNA damage signaling upon USP22 deletion. Data from the IMpower133 clinical trial revealed that a substantial proportion of SCLC patients exhibit KEAP1/NFE2L2 genetic alterations, with activation of an NRF2 transcriptional signature associated with reduced SCLC patient survival with chemotherapy.
2025-03-11 | GSE255095 | GEO