Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transcriptomic profiling of colorectal cancer cells treated with the dual-targeting TOP1/G4 inhibitor ZBH-01

ABSTRACT: Colorectal cancer (CRC) remains a formidable therapeutic challenge due to chemoresistance that limits conventional treatment efficacy. We developed ZBH-01, a first-in-class camptothecin derivative engineered for dual-targeting of topoisomerase I (TOP1) and DNA G-quadruplexes (G4s). Unlike irinotecan (CPT-11), which requires inefficient metabolic activation, ZBH-01 directly stabilizes TOP1-DNA covalent complexes and preferentially binds the hTERT promoter G4, a critical regulator of telomere maintenance and oncogenic transcription. Structural studies reveal the crescent-shaped scaffold of ZBH-01 π-π stacks onto the external G-tetrad of the hTERT G4, displacing SP1/MYC transcription factors and suppressing hTERT expression. Functionally, ZBH-01 demonstrated exceptional efficacy in chemoresistant models, exhibiting 14-fold and 7-fold greater efficacy than CPT-11 and SN-38 respectively in cisplatin-resistant cells, and outperforming CPT-11 by 61-fold and SN-38 by 2.4-fold in 5-FU-resistant models. By concurrently disrupting DNA repair through TOP1-trapping and transcriptional adaptation via G4-stabilization, ZBH-01 induced robust DNA damage, telomere shortening, and cellular senescence. These findings establish TOP1/G4 dual-targeting as a promising therapeutic strategy that enhances CRC chemosensitivity, presenting a new framework for combining DNA damage induction with epigenetic silencing in cancer treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314702 | GEO | 2026/01/30

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

G-quadruplex on Chromosomal DNA Negatively Regulates Topoisomerase 1 Activity [ChIP-seq]

Project description:Human DNA topoisomerase 1 (Top1) is a crucial enzyme responsible for alleviating torsional stress on DNA during transcription and replication, thereby maintaining genome stability. Previous researches had found that non-working Top1 interacted extensively with chromosomal DNA in human cells. However, the reason for its retention on chromosomal DNA remained unclear. In this study, we discovered a close association between Top1 and chromosomal DNA, specifically linked to the presence of G-quadruplex (G4) structures. G4 structures, formed during transcription, trap Top1 and hinder its ability to relax neighboring DNAs. Disruption of the Top1-G4 interaction using G4 ligand relieved the inhibitory effect of G4 on Top1 activity, resulting in a further reduction of R-loop levels in cells. Additionally, the activation of Top1 through the use of a G4 ligand enhanced the toxicity of Top1 inhibitors towards cancer cells. Our study uncovers a negative regulation mechanism of human Top1 and highlights a novel pathway for activating Top1.

2024-01-01 | GSE239692 | GEO

G-quadruplex on Chromosomal DNA Negatively Regulates Topoisomerase 1 Activity [CUT&Tag]

2024-01-01 | GSE239690 | GEO

Proteome-wide Identification of DNA Guanine Quadruplex-binding Proteins

Project description:DNA sequences of high guanine (G) content have the potential to fold into G quadruplex (G4) structures. DNA G4 is known to play important roles in various cellular processes including DNA replication, transcriptional regulation, and maintenance of genomic integrity. A more complete understanding about the biological functions of G4 DNA requires the investigation about how these structures are recognized by cellular proteins. Here, we conducted exhaustive quantitative proteomic experiments to profile the interaction proteomes of three well-defined G4 structures derived from the human telomere and the promoters of cMYC and cKIT genes. Our results led to the identification of a number of candidate G4-interacting proteins; some were previously reported, e.g., FUS, TOP1, and PARP1, and many others were discovered here for the first time. These included three proteins that can bind to all three DNA G4 structures and many proteins that can bind specifically to selected DNA G4 structure(s). We also validated that GRSF1 can bind directly and selectively toward G4 DNA structure derived from the cMYC promoter. Taken together, we uncovered a number of cellular proteins that exhibit general and selective recognitions of G4 folding patterns, which underscore the complexity of G4 DNA in biology and the importance in understanding fully the G4-interaction proteome.

2021-09-29 | PXD026794 | Pride

Topoisomerase I cleavage complexes preferentially down-regulate ubiquitin- and RNA degradation-related transcripts in relationship to gene length, exon-intron junctions and p53-dependent up-regulation of miR-142-3p [miRNA]

Project description:DNA topoisomerase I (Top1) is required for transcription as it relaxes positive and negative supercoils by forming transient Top1 cleavage complexes (Top1cc) up- and down-stream of transcription complexes. However, Top1cc can also be trapped by endogenous DNA lesions and by camptothecin (CPT) and its anticancer derivatives, which results in transcription blocks. Here, we undertook a genome-wide analysis of the effects of CPT on gene expression at exon resolution. We tested the impact of Top1 inhibition on miRNA expression at the genome-wide level in human colon carcinoma HCT116. The miRNA of cells treated with camptothecin (CPT) for were measured at several timepoints with Agilent Human miRNA Microarray V3 (8x15K).

2013-04-17 | E-GEOD-37357 | biostudies-arrayexpress

Expression data from camptothecin-treated rat primary motor neurons

Project description:Topoisomerase 1 (TOP1) poisons like camptothecin (CPT), which are used as chemotherapeutic agents in cancer, elicit DNA damage in quiescient neurons. In this study, we examined the effects of CPT and actinomycin D (ActD) on neuronal cells. Motor (MNs) and cortical (CNs) neurons were more susceptible to the toxic effects of CPT and ActD than fibroblasts. MNs and CNs exhibited a delayed DNA damage response—increase in nuclear γ-H2AX foci—relative to fibroblasts. Neuronal cells expressed higher levels of Top1 mRNA than fibroblasts which could explain their enhanced vulnerability to CPT and ActD toxicity. Microarray analysis was performed to identify differentially regulated transcripts in MNs treated with CPT for 2 hours. Many immediate-early genes including Fos and Egr-1 were upregulated in CPT-treated MNs. Fos mRNA levels were elevated in all cells types treated with CPT; Egr-1 transcript levels, however, were reduced in CPT-treated fibroblasts even though they were elevated in treated MNs and CNs. Pathway and network analysis of the differentially expressed transcripts revealed activation of ERK and JNK signaling cascades in CPT-treated MNs. In conclusion, MNs were more vulnerable than fibroblasts to the damaging effects of TOP1 poisons and they elicit a unique intracellular response to CPT treatment.

2016-09-20 | GSE67146 | GEO

2013-04-17 | GSE37357 | GEO

Transcription poisoning by topoisomerase I is controlled by gene length, splice sites and miR-142-3p

2013-04-17 | GSE37352 | GEO

Transcription poisoning by topoisomerase I is controlled by gene length, splice sites and miR-142-3p

Project description:DNA topoisomerase I (Top1) is required for transcription as it relaxes positive and negative supercoils by forming transient Top1 cleavage complexes (Top1cc) up- and down-stream of transcription complexes. However, Top1cc can also be trapped by endogenous DNA lesions and by camptothecin (CPT) and its anticancer derivatives, which results in transcription blocks. Here, we undertook a genome-wide analysis of the effects of CPT on gene expression at exon resolution. We tested the impact of Top1 inhibition on gene expression at the genome-wide level in human colon carcinoma HCT116 and human breast carcinoma MCF7 cells. The RNA of cells treated with camptothecin (CPT) for various times was analyzed with Affy Exon array (GeneChip Human Exon 1.0 ST array). Moreover, we tested the impact of Top1 down-regulation on gene expression at the genome-wide level in human colon carcinoma HCT116 cells. The RNA of cells treated transfected with a Top1 siRNA was analyzed with Affy Exon array (GeneChip Human Exon 1.0 ST array).

2013-04-17 | E-GEOD-37352 | biostudies-arrayexpress

Irinotecan activates anti-tumor immunity in HCT116 tumor cells

Project description:Topoisomerase I (Top1) is a classical drug target for anticancer therapy, but its role in immune signaling in cancer cells remain unclear. Here, we aimed to explore the possible role and mechanism of Irinotecan (CPT-11) in anti-tumor immunity.

2025-10-18 | GSE245809 | GEO

Irinotecan activates anti-tumor immunity in CT26 subcutaneous tumors

2025-10-16 | GSE245431 | GEO