Transposable elements (TEs) are major contributors to genome plasticity and can reshape gene regulation through stress-responsive activation and the formation of TE-gene chimeric transcripts. Although therapeutic stress is known to perturb transcriptional networks in cancer cells, its impact on canonical TE transcription and TE-gene chimera formation in esophageal squamous cell carcinoma (ESCC) remains poorly defined. To address this, we performed a comprehensive transcriptome-wide analysis of TE expression and TE-gene chimeric transcripts in KYSE150 ESCC cells following combined 125I radiation and carfilzomib treatment. The TE analysis showed 148 dysregulated TEs, characterized by ERV1 LTR element enrichment and distinct treatment-control sample separation, indicating structured remodeling of the TE transcriptome. We identified 301 significant TE-gene chimeric events, indicating category-specific remodeling with an increase in TE-initiated and TE-exonic chimeras and a decrease in TE-terminal events. The TE families that underwent the most transcriptional changes were not those that drove chimeric events, indicating that global TE activation does not passively cause chimera remodeling. The gene repression was strongly associated with chimeric transcripts, and gene expression changes were negatively correlated with chimerism frequency. SPANXN1, IL1RL1, and RSAD2, strongly downregulated genes, produced novel TE-derived isoforms and were high-potential functional candidates. Epigenetic context analysis showed considerable overlap between exonized chimeras and candidate cis-regulatory elements, suggesting a potential association with regulatory genomic contexts. Pathway enrichment analysis showed synchronized transcriptomic reprogramming and cell cycle and DNA repair pathway activation and autophagy inhibition. In esophageal cancer cells, concurrent genotoxic and proteotoxic stress causes complex TE remodeling, linking traditional TE transcriptional alterations to structured TE-gene chimera development and stress-related transcriptome reprogramming.

Background: The dysregulation of the CDK1/Cyclin B1 complex drives tumor progression in breast cancer (BC). The natural flavonoid luteolin (LT) shows anti-cancer potential, but its mechanism targeting CDK1/CCNB1 remains unclear. Methods: CDK1, CCNB1, and CCNB2 expression were profiled in normal and BC cell lines. An engineered HEK293T GST-CDK1/CCNB1 cell model was used to evaluate LT’s effects on proliferation, ROS levels, and target gene transcription. Computational approaches (molecular docking, dynamics simulations, pharmacophore modeling, MM/GBSA, ADMET, and network pharmacology) assessed LT and its analogues. Results: CDK1/CCNB1 expression was lower in MCF7 BC cells than in normal cells, suggesting the loss of a growth barrier. In engineered HEK293T cells, LT suppressed CCNB1 transcription with minimal effect on CDK1 levels, correlating with anti-proliferative and ROS-modulating effects. Computational analyses confirmed stable LT binding to the CDK1/CCNB1 complex. Designed LT analogues showed improved binding and favorable ADMET profiles. Network pharmacology identified cell cycle regulation, particularly in BC stem cells, as the primary pathway targeted. Conclusions: LT and its analogues inhibit the CDK1/Cyclin B1 complex, revealing a dual mechanism that suppresses both tumor growth and BC stemness.

Apigenin, a naturally occurring flavonoid with low toxicity, exhibits anticancer activity, yet its effects on microRNAs (miRNAs) and downstream gene networks in esophageal squamous cell carcinoma (ESCC) remain unclear. Here, we evaluated apigenin’s antitumor effects in TE-1 and Eca-109 cells, assessing proliferation, apoptosis, colony formation, and invasion. Differentially expressed miRNAs were identified via small RNA sequencing, and candidate target genes were predicted, annotated using GO and KEGG analyses, and validated by qRT-PCR, revealing miRNA-mediated regulatory mechanisms underlying apigenin’s inhibitory effects in ESCC. Apigenin markedly suppressed cell proliferation, clonogenic growth, wound closure, and invasive capacity, while promoting apoptosis in a dose-dependent manner. In TE-1 cells, apigenin upregulated hsa-let-7c-3p, hsa-miR-374c-3p, hsa-miR-3177-3p hsa-miR-4454, and hsa-miR-4728-3p, while downregulating hsa-miR-573, hsa-miR-548az-5p, hsa-miR-33b-5p, hsa-miR-4479, and hsa-miR-3198. Correspondingly, tumor-associated target genes including ALDH3A2, SEMA3F, MAP4K5, and TRIP13 were upregulated, whereas PIK3IP1, AGO2, MMP2, and RALBP1 were suppressed. In Eca-109 cells, apigenin altered the expression of distinct miRNAs, including the upregulation of hsa-miR-891-5p, hsa-miR-3170, hsa-miR-4421, and hsa-miR-675-5p and the downregulation of hsa-miR-153, hsa-miR-3188, and hsa-miR-4435, thereby modulating key oncogenic targets such as MAPK1, SALL4, and COX15. Functional enrichment analyses indicated that apigenin-regulated genes are involved in multiple cancer-related pathways across cytoplasmic and nuclear compartments. Overall, these results suggest that apigenin suppresses ESCC progression via coordinated miRNA–mRNA regulation, highlighting its potential as a therapeutic agent.