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

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

PROVIDER: PRJNA939626 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23641862.fastq.gz	Fastqsanger.gz
	SRR23641863.fastq.gz	Fastqsanger.gz
	SRR23641864.fastq.gz	Fastqsanger.gz
	SRR23641865.fastq.gz	Fastqsanger.gz
	SRR23641866.fastq.gz	Fastqsanger.gz

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Similar Datasets

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 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 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 downregulation 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 upstream 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 upregulation 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 downregulate 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.

| S-EPMC10051992 | biostudies-literature

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

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

| PRJNA1133697 | ENA

G-Quadruplex structures are stable and detectable in human genomic DNA.

Project description:The G-quadruplex is an alternative DNA structural motif that is considered to be functionally important in the mammalian genome. Herein, we address the hypothesis that G-quadruplex structures can exist within double-stranded genomic DNA using a G-quadruplex-specific probe. An engineered antibody is employed to enrich for DNA containing G-quadruplex structures, followed by deep sequencing to detect and map G-quadruplexes at high resolution in genomic DNA from human breast adenocarcinoma cells. Our high sensitivity structure-based pull-down strategy enables the isolation of genomic DNA fragments bearing a single as well as multiple G-quadruplex structures. Stable G-quadruplex structures are found in sub-telomeres, gene bodies and gene regulatory regions. For a sample of identified target genes, we show that G-quadruplex stabilizing ligands can modulate transcription. These results confirm the existence of G-quadruplex structures and their persistence in human genomic DNA. Four independent libraries have been enriched in DNA G-quadruplex structures using a G-quadruplex-specific probe. One genomic input library was sequenced as control. Deep-sequencing of these libraries allowed the mapping of G-quadruplexes on the genome.

2013-05-08 | E-GEOD-45241 | biostudies-arrayexpress

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

Structure-activity relationships for the G-quadruplex-targeting experimental drug QN-302 and two analogues probed with comparative transcriptome profiling and molecular modeling.

Project description:The tetrasubstituted naphthalene diimide compound QN-302 binds to G-quadruplex (G4) DNA structures. It shows high potency in pancreatic ductal adenocarcinoma (PDAC) cells and inhibits the transcription of cancer-related genes in these cells and in PDAC animal models. It is currently in Phase 1a clinical evaluation as an anticancer drug. A study of structure-activity relationships of QN-302 and two related analogues (CM03 and SOP1247) is reported here. These have been probed using comparisons of transcriptional profiles from whole-genome RNA-seq analyses, together with molecular modelling and molecular dynamics simulations. Compounds CM03 and SOP1247 differ by the presence of a methoxy substituent in the latter: these two compounds have closely similar transcriptional profiles. Whereas QN-302 (with an additional benzyl-pyrrolidine group), although also showing down-regulatory effects in the same cancer-related pathways, has effects on distinct genes, for example in the hedgehog pathway. This distinctive pattern of genes affected by QN-302 is hypothesized to contribute to its superior potency compared to CM03 and SOP1247. Its enhanced ability to stabilize G4 structures has been attributed to its benzyl-pyrrolidine substituent fitting into and filling most of the space in a G4 groove compared to the hydrogen atom in CM03 or the methoxy group substituent in SOP1247.

| S-EPMC10859377 | biostudies-literature

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

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