PRMT1 is a critical dependency in clear cell renal cell carcinoma through its role in RNA metabolism and the DNA damage response
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive HF
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Brian Raught
PROVIDER: MSV000094655 | MassIVE | Wed May 01 13:50:00 BST 2024
SECONDARY ACCESSION(S): PXD051931
REPOSITORIES: MassIVE
Similar Datasets
Project description:Renal cell carcinoma (RCC) is the most lethal type of cancer in the urinary system and often presents as a metastatic disease. Furthermore, there are no effective treatments for the disease. Several studies based on gene expression profiling have been performed with the aim of gaining insights into the pathogenesis of RCC; however, few studies have investigated RCC at the pathway level to search for the possible pathways involved in clear cell RCC (CCRCC). In this study, gene set enrichment analysis (GSEA) was conducted on microarray datasets from CCRCC tissue. DAVID functional enrichment analysis was performed based on the dysregulated genes that were identified in a meta-analysis performed on the microarray datasets from CCRCC tissue. In GSEA, 17 down- and 12 upregulated pathways coexisted in six datasets. The majority of the upregulated pathways were associated with the immune system. In addition, 32 dysregulated pathways were obtained from DAVID functional enrichment analysis, based on the abnormal genes identified by meta-analysis. This study demonstrated that cross-GSEA is a useful method for exploring the critical pathways involved CCRCC; however, an individual dataset with a small sample may introduce bias. A cross-GSEA based on certain well-designed datasets may be required to further the progress made in this study, following the analysis of its results.
| S-EPMC3861490 | biostudies-literature
Project description:Increasing data implicate iron accumulation in tumorigenesis of the kidney, particularly the clear cell renal cell carcinoma (ccRCC) subtype. The von Hippel Lindau (VHL)/hypoxia inducible factor-α (HIF-α) axis is uniquely dysregulated in ccRCC and is a major regulator and regulatory target of iron metabolism, yet the role of iron in ccRCC tumorigenesis and its potential interplay with VHL inactivation remains unclear. We investigated whether ccRCC iron accumulation occurs due to increased cell dependency on iron for growth and survival as a result of VHL inactivation. Free iron levels were compared between four VHL-mutant ccRCC cell lines (786-0, A704, 769-P, RCC4) and two benign renal tubule epithelial cell lines (RPTEC, HRCEp) using the Phen Green SK fluorescent iron stain. Intracellular iron deprivation was achieved using two clinical iron chelator drugs, deferasirox (DFX) and deferoxamine (DFO), and chelator effects were measured on cell line growth, cell cycle phase, apoptosis, HIF-1α and HIF-2α protein levels and HIF-α transcriptional activity based on expression of target genes CA9, OCT4/POU5F1 and PDGFβ/PDGFB. Similar assays were performed in VHL-mutant ccRCC cells with and without ectopic wild-type VHL expression. Baseline free iron levels were significantly higher in ccRCC cell lines than benign renal cell lines. DFX depleted cellular free iron more rapidly than DFO and led to greater growth suppression of ccRCC cell lines (>90% at ~30-150 µM) than benign renal cell lines (~10-50% at up to 250 µM). Similar growth responses were observed using DFO, with the exception that a prolonged treatment duration was necessary to deplete cellular iron adequately for differential growth suppression of the less susceptible A704 ccRCC cell line relative to benign renal cell lines. Apoptosis and G1-phase cell cycle arrest were identified as potential mechanisms of chelator growth suppression based on their induction in ccRCC cell lines but not benign renal cell lines. Iron chelation in ccRCC cells but not benign renal cells suppressed HIF-1α and HIF-2α protein levels and transcriptional activity, and the degree and timing of HIF-2α suppression correlated with the onset of apoptosis. Restoration of wild-type VHL function in ccRCC cells was sufficient to prevent chelator-induced apoptosis and G1 cell cycle arrest, indicating that ccRCC susceptibility to iron deprivation is VHL inactivation-dependent. In conclusion, ccRCC cells are characterized by high free iron levels and a cancer-specific dependency on iron for HIF-α overexpression, cell cycle progression and apoptotic escape. This iron dependency is introduced by VHL inactivation, revealing a novel interplay between VHL/HIF-α dysregulation and ccRCC iron metabolism. Future study is warranted to determine if iron deprivation using chelator drugs provides an effective therapeutic strategy for targeting HIF-2α and suppressing tumor progression in ccRCC patients.
| S-EPMC10038186 | biostudies-literature
Project description:DNA damage repair plays an important role in cancer's initiation and progression, and in therapeutic resistance. The prognostic potential of damage repair indicators was studied in the case of clear cell renal cell carcinoma (ccRCC). Gene expression profiles of the disease were downloaded from cancer genome databases and gene ontology was applied to the DNA repair-related genes. Twenty-six differentially expressed DNA repair genes were identified, and regression analysis was used to identify those with prognostic potential and to construct a risk model. The model accurately predicted patient outcomes and distinguished among patients with different expression levels of immune evasion genes. The data indicate that DNA repair genes can be valuable for predicting the progression of clear cell renal cell carcinoma and the clinical benefits of immunotherapy.
| S-EPMC7820869 | biostudies-literature
Project description:Clear cell papillary renal cell carcinoma (CCPRCC) is a low-grade renal neoplasm with morphological characteristics mimicking both clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC). However, despite some overlapping features, their morphological, immunohistochemical, and molecular profiles are distinct. Micro-RNAs (miRNAs) are small noncoding RNAs that play a crucial role in regulating gene expression and are involved in various biological processes, including cancer development. To better understand the biology of this tumor, we aimed to analyze the miRNA expression profile of a set of CCPRCC using microarray and quantitative reverse transcription-polymerase chain reaction. A total of 15 cases diagnosed as CCPRCC were used in this study. Among the most differentially expressed miRNA in CCPRCC, we found miR-210, miR-122, miR-34a, miR-21, miR-34b*, and miR-489 to be up-regulated, whereas miR-4284, miR-1202, miR-135a, miR-1973, and miR-204 were down-regulated compared with normal renal parenchyma. To identify consensus of differentially regulated miRNA between CCPRCC, CCRCC, and PRCC, we additionally determined differential miRNA expression using 2 publically available microarray data sets from the NCBI Gene Expression Omnibus database (GSE41282 and GSE3798). This comparison revealed that the miRNA expression profile of CCPRCC shows some overlapping characteristics between CCRCC and PRCC. Moreover, CCPRCC lacks dysregulation of important miRNAs typically associated with aggressive behavior. In summary, we describe the miRNA expression profile of a relatively infrequent type of renal cancer. Our results may help in understanding the molecular underpinning of this newly recognized entity.
| S-EPMC4332813 | biostudies-literature
Project description: Not available
| S-EPMC10848511 | biostudies-literature
Project description:In addition to the ubiquitous loss of the VHL gene in clear cell renal cell carcinoma (ccRCC), co-deletions of chromatin-regulating genes are common drivers of tumorigenesis, suggesting potential vulnerability to epigenetic manipulation. A library of chemical probes targeting a spectrum of epigenetic regulators is screened using a panel of ccRCC models. MS023, a type I protein arginine methyltransferase (PRMT) inhibitor, is identified as an antitumorigenic agent. Individual knockdowns indicate PRMT1 as the specific critical dependency for cancer growth. Further analyses demonstrate impairments to cell cycle and DNA damage repair pathways upon MS023 treatment or PRMT1 knockdown. PRMT1-specific proteomics reveals an interactome rich in RNA binding proteins and further investigation indicates significant widespread disruptions in mRNA metabolism with both MS023 treatment and PRMT1 knockdown, resulting in R-loop accumulation and DNA damage over time. Our data supports PRMT1 as a target in ccRCC and informs a mechanism-based strategy for translational development.
| S-EPMC11413393 | biostudies-literature
Project description:The aims of the study was to explore the tumor proteome of patients diagnosed with localized ccRCC and treated with surgery and the identification of altered pathways that could be the target of new treatments. A total of 165 FFPE tumor samples from patients diagnosed with ccRCC were analyzed using DIA-proteomics. Proteomics ccRCC subtypes were defined using a Consensus Cluster Algorithm (CCA) and characterized by a functional approach using probabilistic graphical models and survival analyses. Two proteomics subtypes of ccRCC (CCA1 and CCA2) were identified by CCA using the high confidence proteins only. Characterization of molecular differences between CCA1 and CCA2 was performed in two steps. First, we defined 514 proteins showing differential expression between the two subtypes using a significance analysis of microarrays analysis. Proteins overexpressed in CCA1 were mainly related to translation and ribosome, while proteins overexpressed in CCA2 were mainly related to focal adhesion and membrane. Second, a functional analysis using probabilistic graphical models was performed. The CCA1 subtype is characterized by an increased expression of proteins related to glycolysis, mitochondria, translation, adhesion proteins related to cytoskeleton and actin, nucleosome, and spliceosome, while CCA2 subtype showed higher expression o proteins involved in focal adhesion, extracellular matrix and collagen organization.
2025-05-09 | PXD039258 | Pride
Project description:The treatment of advanced and metastatic kidney cancer has been revolutionized by the development of targeted systemic therapies. Despite the growing number of available agents approved for use against clear cell renal cell carcinoma, patients with non-clear histologies, constituting approximately 1 in 4 cases of kidney cancer, have not received the same attention. The majority of clinical trials testing novel targeted therapies have excluded non-clear subtypes, providing limited therapeutic options for patients with these diagnoses and their oncologists. This review will focus on the use of targeted therapies against the non-clear histologic subtypes of renal cell carcinoma: papillary I and II, chromophobe, and collecting duct. The unique genetic and molecular profiles of each distinct non-clear kidney cancer subtype will be described, as these differences are integral to the development and effectiveness of the novel agents used to treat them. Trials focusing on non-clear kidney cancer, or those that treated clear cell tumors along with significant numbers of non-clear subtypes, will be discussed. The role of cytoreductive nephrectomy and the use of neoadjuvant and adjuvant targeted therapy will be reviewed. Lastly, areas of future research will be highlighted.
| S-EPMC3003336 | biostudies-other
Project description:Immune checkpoint inhibitors (ICIs) have transformed the management of advanced renal cell carcinoma (RCC), but most patients still do not receive a long-term benefit from these therapies, and many experience off-target, immune-related adverse effects. RCC is also different from many other ICI-responsive tumors, as it has only a modest mutation burden, and total neoantigen load does not correlate with ICI response. In order to improve the efficacy and safety of immunotherapies for RCC, it is therefore critical to identify the antigens that are targeted in effective anti-tumor immunity. In this review, we describe the potential classes of target antigens, and provide examples of previous and ongoing efforts to investigate and target antigens in RCC, with a focus on clear cell histology. Ultimately, we believe that a concerted antigen discovery effort in RCC will enable an improved understanding of response and resistance to current therapies, and lay a foundation for the future development of "precision" antigen-directed immunotherapies.
| S-EPMC10475986 | biostudies-literature
Project description:The dual immune checkpoint blockade targeting CTLA-4 and PD-1 (ipilimumab/nivolumab) or the IO combinations targeting PD-1 and anti-VEGF TKIs (pembrolizumab/axitinib, nivolumab/cabozantinib, pembrolizumab/lenvatinib) have demonstrated an overall survival benefit in advanced clear cell renal cell carcinoma (ccRCC). Despite this significant improvement in clinical outcomes in the frontline setting from IO/IO or the IO/TKI combinations, there is a subset of patients of advanced ccRCC that do not respond to such combinations or will lose the initial efficacy and have disease progression. Therefore, a remarkable unmet need exists to develop new therapeutics to improve outcomes. With an enhanced understanding of ccRCC biology and its interaction with the tumor microenvironment, several new therapies are under development targeting ccRCC metabolism, cytokine-signaling, alternative immune checkpoint proteins, and novel biological pathways. In addition, microbiome products enhancing IO response, antibody-drug conjugates, and targeted radionuclides are also being investigated. This review summarizes selected emerging agents that are under development in ccRCC.
| S-EPMC9561986 | biostudies-literature