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The G-Quadruplex experimental drug QN-302 effectively impairs liposarcoma cell viability by inhibiting MDM2 expression and restoring p53 levels [RNA-seq]

ABSTRACT: The G-Quadruplex experimental drug QN-302 effectively impairs liposarcoma cell viability by inhibiting MDM2 expression and restoring p53 levels [RNA-seq]

PROVIDER: PRJNA1133697 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29755872.fastq.gz	Fastqsanger.gz
	SRR29755873.fastq.gz	Fastqsanger.gz
	SRR29755874.fastq.gz	Fastqsanger.gz
	SRR29755875.fastq.gz	Fastqsanger.gz
	SRR29755876.fastq.gz	Fastqsanger.gz

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The G-Quadruplex experimental drug QN-302 effectively impairs liposarcoma cell viability by inhibiting MDM2 expression and restoring p53 levels [RNA-seq]

Project description:Well-differentiated (WD) and dedifferentiated (DD) liposarcomas (LPS) account for ~60% of all liposarcomas, characterized by 12q13–q15 region amplification and aberrant MDM2 expression. Current therapies are limited, particularly for advanced stages, leading to poor outcomes. G-quadruplexes (G4s), secondary structures in G-rich nucleic acid sequences, were identified in the MDM2 P2 promoter. We investigated MDM2 inhibition via small molecule G4 ligands. Laboratory and patient-derived LPS cell lines, and normal pre-adipocytes were analyzed using CUT&Tag, RNA-seq, cell viability, qRT-PCR, Western blot, siRNA, and nascent transcript assays. QN-302, a naphthalene diimide (NDI)-derivative, emerged as the most effective G4 ligand, significantly impairing WD/DDLPS cell growth in a dose-dependent manner by stabilizing MDM2 G4 at the P2 promoter, inhibiting polymerase progression, and reducing full-length MDM2 transcripts, leading to p53 accumulation and apoptotic cell death. In vivo, QN-302 reduced tumor volume and was well-tolerated in xenograft models. This novel therapeutic strategy to inhibit MDM2 and reactivate p53 in WD/DDLPS could extend to all tumors with wild-type TP53 and enhance anticancer efficacy when combined with other drugs.

2025-01-31 | GSE271823 | GEO

The G-Quadruplex experimental drug QN-302 effectively impairs liposarcoma cell viability by inhibiting MDM2 expression and restoring p53 levels [CUT&Tag]

2025-01-31 | GSE271822 | GEO

The G-Quadruplex experimental drug QN-302 effectively impairs liposarcoma cell viability by inhibiting MDM2 expression and restoring p53 levels [CUT&Tag]

Project description:The G-Quadruplex experimental drug QN-302 effectively impairs liposarcoma cell viability by inhibiting MDM2 expression and restoring p53 levels [CUT&Tag]

| PRJNA1133696 | ENA

The Potent G-Quadruplex-Binding Compound QN-302 Downregulates S100P Gene Expression in Cells and in an In Vivo Model of Pancreatic Cancer

Project description:The naphthalene diimide compound QN-302, designed to bind to G-quadruplex DNA sequences within the promoter regions of cancer-related genes, has high anti-proliferative activity in pancreatic cancer cell lines and anti-tumor activity in several experimental models for the disease. We show here that QN-302 also causes down-regulation of the expression of the S100P gene and the S100P protein in cells and in vivo. This protein is well-established as being involved in key proliferation and motility pathways in several human cancers and has been identified as a potential biomarker in pancreatic cancer. The S100P gene contains 60 putative quadruplex-forming sequences, one of which is in the promoter region, 48 nucleotides up-stream from the transcription start site. We report biophysical and molecular modeling studies showing that this sequence forms a highly stable G-quadruplex in vitro, which is further stabilized by QN-302. We also report transcriptome analyses showing that S100P expression is highly upregulated in tissues from human pancreatic cancer tumors, compared to normal pancreas material. The extent of up-regulation is dependent on the degree of differentiation of tumor cells, with the most poorly differentiated, from more advanced disease, having the highest level of S100P expression. The experimental drug QN-302 is currently in pre-IND development (as of Q1 2023) and its ability to down-regulate S100P protein expression supports a role for this protein as a marker of therapeutic response in pancreatic cancer. These results are also consistent with the hypothesis that the S100P promoter G-quadruplex is a potential therapeutic target in pancreatic cancer at the transcriptional level for QN-302.

2023-04-01 | GSE226307 | GEO

The G-quadruplex experimental drug QN-302 impairs liposarcoma cell growth by inhibiting MDM2 expression and restoring p53 levels.

Project description:Well-differentiated/dedifferentiated liposarcomas (WD/DDLPSs) account for ∼60% of all liposarcomas. They have a poor prognosis due to limited therapeutic options. WD/DDLPSs are characterized by aberrant expression of mouse double minute 2 (MDM2), which forms G-quadruplexes (G4s) in its promoter. Here, we investigated the possibility of targeting WD/DDLPSs with small molecules against the MDM2 G4s. Among the molecules tested, the naphthalene diimide derivative QN-302 significantly impaired WD/DDLPS cell growth and its activity strikingly paralleled cell-specific G4 abundance as measured by CUT&Tag and RNA sequencing analysis. QN-302 stabilized MDM2 G4s at the P2 inducible promoter and prevented polymerase progression from the constitutive P1 promoter, thereby inhibiting the formation of full-length MDM2 transcripts. This resulted in the accumulation of p53 through the p53-MDM2 autoregulatory feedback loop, ultimately leading to apoptotic cell death. In patient-derived xenograft mouse models, QN-302 treatment reduced tumour volume distribution and was well tolerated. We have identified a novel and effective therapeutic strategy to reduce MDM2 expression and promote p53 reactivation in tumours harbouring wild-type TP53, such as WD/DDLPSs.

| S-EPMC11822379 | biostudies-literature

miRNA analyses of genetic factors and the role of carotenoid accumulation in adductor muscles of QN Orange scallops

Project description:QN Orange scallop was interspecific hybrids with orange adductor muscles. Previous studies shown the accumulation of carotenoids was present in QN Orange scallops. In this study, analysis of miRNA expression profiles was performed to explore possibly regulatory patterns in carotenoid accumulation in adductor muscles of QN Orange scallops. Based on small RNA sequencing, a total of 3289 miRNAs and 91 differential expression miRNAs were identified between white and orange adductor muscles, respectively. GO and KEGG enrichment analysis of target genes of DE miRNA enriched in the transmembrane transporter activity-related pathways, kinase activity-related pathways, signal transduction-related pathways, ABC transporters, Retinol metabolism, lipid related metabolism and calcium signaling pathway.

2024-11-10 | GSE248569 | GEO

miR-302-367 regulates cardiomycyte proliferation and differentiation during development

Project description:To define the role of miR-302-367 cluster in cardiac development, we overexpressed miR-302-367 cluster in mouse heart by using R26R-miR-302-367; Nkx2.5-Cre mice. This data set contains the microarrays examining gene expression in the hearts of R26R-miR-302-367; Nkx2.5-Cre mice at postnatal day 14.

2015-01-01 | GSE54988 | GEO

miR-302-367 regulates cardiomycyte proliferation and differentiation during development

2015-01-01 | E-GEOD-54988 | biostudies-arrayexpress

The Potent G-Quadruplex-Binding Compound QN-302 Downregulates S100P Gene Expression in Cells and in an In Vivo Model of Pancreatic Cancer

Project description:The Potent G-Quadruplex-Binding Compound QN-302 Downregulates S100P Gene Expression in Cells and in an In Vivo Model of Pancreatic Cancer

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Whole genome microarray analysis in myxoid liposarcoma

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2014-10-28 | GSE62747 | GEO

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