TOP2A (DNA topoisomerase 2-alpha)

The resulting splice site gene-edited clone, designated MX2/SS-Edit, expressed reduced TOP2α/160 mRNA/protein, increased TOP2α/170 mRNA/protein, and exhibited partial restoration of sensitivity to mitoxantrone, etoposide, and amsacrine. SIGNIFICANCE STATEMENT: Results presented here validated drug resistance in the HL-60/MX2 leukemia cell line driven by intronic polyadenylation (IPA) within intron 33 of the DNA topoisomerase IIα (TOP2α) gene, which produced a truncated and predominantly cytoplasmic TOP2α protein isoform (TOP2α/160). Using CRISPR/Cas9/homology-directed repair gene editing, the weak exon 33/intron 33 5' splice site was enhanced to suppress IPA, which restored expression of full-length protein (TOP2α/170) and led to a gain-of-function in drug sensitivity, offering a potential strategy to overcome drug resistance.

Redocking of co-crystallized ligands yielded RMSD values below 2.0 Å, supporting protocol reliability. Overall, these findings suggest preliminary dark-condition in vitro activity of SiPc (Tan et al., 2020 (4)) and SubPc (Weller et al., 2021 (5)) against U-87 MG cells, while the docking results offer hypothesis-generating molecular insight into possible target interactions that may support future mechanistic and optimization studies.

This integrative study provides a comprehensive single‑cell and spatial atlas of baicalein‑responsive genes in NSCLC, identifies a robust diagnostic signature, and offers mechanistic insights for developing baicalein as a potential therapeutic agent.

Topoisomerase II (TOP2) poisons, such as etoposide, are potent antineoplastic drugs that also cause significant secondary toxicity to postmitotic cells...Intriguingly, HSF1 preferentially stimulates TOP2B over TOP2A, and knockdown or inhibition of HSF1 reduces the levels of catalytically engaged TOP2B but not TOP2A. Moreover, HSF1 inhibitors suppress the cytotoxicity of TOP2 poisons toward postmitotic cells without compromising their ability to kill cancer cells, revealing a strategy for minimizing the side-effects of TOP2 poison-based chemotherapy.

Variant T-allele carriers (CT or TT) exhibited approximately 30% lower DOX EC50 than CC homozygotes in both the training and the test sets. Comprehensive analysis of common diversity in genetic loci coding for human topoisomerases identified rs113270903 in TOP3A as a new promising determinant of DOX sensitivity.

This study presents a lactylation-related risk score model with significant potential for improving the management of PDAC patients. The identification of the lactate-TOP2A-H3K18la-NQO1 axis enhances the understanding of lactylation mechanisms in PDAC, thereby providing a foundation for targeted therapeutic approaches.

While ICRF-193 suppressed tumor growth, Top2βf/f deficiency (with a compensatory TOP2α upregulation) enhanced tumor development, indicating potential roles for TOP2 isozymes in tumor formation and progression. Collectively, these findings identify the cooperative action of TOP2 and NOS2 in driving DSBs, highlighting a potential therapeutic target in inflammation-associated CRC.

The experimental results demonstrated that both hit compounds effectively exhibited significant anti-proliferative activities against the HepG2 cell line, with IC50 values of 9.54 ± 0.26 µg mL-1 (CID162372098) and 10.03 ± 0.36 12.69 ± 0.31 µg mL-1 (CID156619937), respectively. Collectively, these findings demonstrate the potential of xanthone-based scaffolds as inhibitors of TOP2A and provide a rational framework for the screening and development of novel anticancer agents.

Drug-gene correlation analysis revealed positive associations of TOP2A and RACGAP1 with sensitivity to mitogen-activated protein kinase inhibitors and negative correlations with several targeted inhibitors. The identified prognostically unfavorable hub genes in HBV/HCV-associated HCC are associated with an immunosuppressive microenvironment and with patterns of drug sensitivity.

Querying the Connectivity Map/LINCS library with the human component of the module highlighted anthracycline-like topoisomerase II poisons (valrubicin, etoposide, amsacrine) and the PARP inhibitor rucaparib among the ~0.2% most negative connectivity scores, while directly targeting TOP2A and/or PARP1. Finally, extracellular-vesicle microRNA (EV-miRNA) profiling in human DLBCL showed that differentially expressed EV-miRNAs, including let-7 family members, miR-21-5p, miR-124-3p and miR-205-5p, converge on the same TOP2A/PARP1-centred core. These cross-species, multi-layer data support topoisomerase II poisons and PARP inhibition as coherent, network-anchored candidate therapies for canine DLBCL, with module scores and EV-miRNAs as candidate biomarkers.

Follow-up 18F-FDG PET/CT confirmed a sustained partial response per response evaluation criteria in solid tumors (RECIST) 1.1, accompanied by significant metabolic improvement with regression of metastatic burden with evident central photopenia in peritoneal lesions. This case illustrates how multi-faceted genomic analysis can rationalize aggressive combination immunotherapy in refractory ACC.

Seven ARGs were identified as key prognostic markers in ccRCC. A robust risk model was established, providing insights into ARG-related mechanisms and potential diagnostic and therapeutic strategies.