Jul 2026· International Journal of Biological Macromolecules· pp.
153508
· 0 citations· 48 references
Medicine
TL;DR
These findings establish CTD-2566 J3.1 as a multifunctional enhancer-associated lncRNA (e-lncRNA) that orchestrates key oncogenic processes in luminal breast cancer and underscores the utility of three-dimensional culture systems to reveal context-specific lncRNA functions.
Abstract
Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of gene expression and genome architecture in cancer. By scaffolding chromatin-modifying protein complexes and mediating enhancer-promoter communication, lncRNAs can shape transcriptional programs that sustain tumor growth. In this study, we investigated the functional role of CTD-2566 J3.1, an antisense lncRNA located within the RAD51B locus that carries enhancer-associated chromatin marks, including H3K27ac and H3K4me1, in luminal breast cancer cells. Using chromatin conformation capture experiments (4C-seq), we identified recurrent long-range chromatin interactions linking the CTD-2566 J3.1 locus to regulatory elements within three distant genes with established roles in cancer biology: RAD51B, MAP3K9, and ACTN1. These genomic regions were enriched for estrogen receptor (ESR1) and FOXA1 binding sites, suggesting hormone-responsive regulation. Interestingly, in three-dimensional spheroids, these genes were consistently more expressed than in monolayer cultures, underscoring the importance of microenvironmental context for transcriptional regulation in breast cancer. Functionally, loss of CTD-2566 J3.1 impaired cell proliferation and invasion and increased endogenous DNA damage. Our findings establish CTD-2566 J3.1 as a multifunctional enhancer-associated lncRNA (e-lncRNA) that orchestrates key oncogenic processes in luminal breast cancer. Additionally, this work underscores the utility of three-dimensional culture systems to reveal context-specific lncRNA functions and highlights CTD-2566 J3.1 as a potential regulator and therapeutic target in breast cancer.
This study uncovers a therapeutic vulnerable lncRNA-centric circuitry and provides compelling preclinical evidence for the development and application of a novel RNA targeting-LNP based therapy for treatment of myeloid leukemia.
Zhenggen Jin, Brendan D. Ma, Karen Y. T. Chan et al.· bioRxiv· 0 citations
Colorectal cancer (CRC) is a prevalent malignancy with a complex genetic basis. Recent genome-wide association studies (GWAS) have identified a susceptibility locus at 3p21.31, however, the functional SNP(s) underlying the association between the 3p21.31 region and CRC remain to be elucidated. In this study, we identified rs2101247 as the potential functional SNP and further demonstrated that rs2101247 is significantly associated with the expression of the nearby long non-coding RNA (lncRNA) RP11-708J19.2 (ENSG00000271161.1). Functional experiments showed that RP11-708J19.2 is upregulated in CRC tumor tissues, and its knockdown reduces cell viability while promoting apoptosis in SW1116 and HCT116 cell lines. Mechanistically, RP11-708J19.2 interacts directly with the deacetylase SIRT7, modulating histone H3K18 acetylation (H3K18ac). Specifically, RP11-708J19.2 knockdown leads to a significant upregulation of H3K18ac levels, implicating a SIRT7-mediated epigenetic pathway in CRC progression. Our findings elucidate a novel functional SNP-lncRNA axis that contributes to CRC pathogenesis, providing potential biomarkers for early detection and therapeutic targets for intervention.
Jiali Ma, Xianglong Tian, Yiwen Qiu et al.· European Journal of Histoche...· 0 citations
Findings indicate that RP3-340N1.2 is aberrantly expressed in LUAD and may participate in tumor-associated cellular behaviors through a miR-4650-5p/SHC1-related regulatory mechanism.
Fang Chen, Yan Yan, Wenting Yang et al.· PLoS ONE· 0 citations
A mechanism wherein SChLAP1 modulates AR signaling to promote PCa growth and progression is suggested, suggesting its molecular mechanism and potential to be used as a therapeutic target or biomarker.
Lung cancer remains the leading cause of cancer-related death worldwide, and long noncoding RNAs (lncRNAs) have been implicated in its tumourigenesis and progression. However, the roles lncRNAs play in lung cancer remain unclear. In this study, we discovered an important role for the lncRNA MNX1 Antisense RNA 1 (MNX1-AS1) as a critical regulator of one-carbon metabolism reprogramming. Glutamine depletion altered chromatin accessibility, leading to downregulation of MNX1-AS1, while elevated expression of MNX1-AS1 was correlated with poor prognosis in patients with non-small cell lung cancer. Functional studies showed that MNX1-AS1 promoted cell proliferation and sphere formation in vitro, and subcutaneous and orthotopic tumour growth in vivo. Mechanistically, MNX1-AS1 directly binds to calcyclin binding protein (CACYBP), protecting it from ubiquitin-mediated degradation; thus, the MNX1-AS1/CACYBP complex accelerates the transcription of key one-carbon metabolism-related genes through the Wnt/β-catenin pathway. MNX1-AS1/CACYBP/β-catenin axis upregulated key one-carbon metabolism-related genes, which were essential for generating related metabolites and maintaining cellular redox balance to support lung cancer cell proliferation. These findings established that the lncRNA MNX1-AS1 acts as a crucial driver of one-carbon metabolism reprogramming in non-small cell lung cancer and highlight that the newly identified MNX1-AS1/CACYBP/β-catenin axis may serve as a potential prognostic biomarker and therapeutic target for lung cancer intervention.
Juze Yang, Xinyi Qian, Jiayi Ren et al.· Cell Death and Differentiati...· 0 citations
Lineage-determining transcription factors (TFs), such as p63 in epithelial tissues, establish normal tissue identity but can also drive carcinogenesis. The epigenetic basis for these divergent effects, however, is unclear. Here, we show that p63 reorganizes three-dimensional (3D) chromatin topology in squamous cell carcinoma (SCC) through cooperation with the tumor-selective partner TF, FOXK1. Multi-omic profiling across normal and malignant states reveals that p63 enhances connectivity between cis-regulatory elements near oncogenes and promotes a secondary enhancer looping architecture, in which p63 and FOXK1-enriched enhancers indirectly contact target promoters via FOXK1-associated intermediate anchors lacking p63 binding. FOXK1 mediates p63-dependent chromatin looping, as FOXK1 loss selectively weakens p63-dependent loops and reduces transcription of associated target genes. The p63–FOXK1 interaction is observed in human tumor samples but not in normal tissues. Together, our findings define an epigenetic mechanism by which a lineage master TF and tumor-restricted partner TF reshape 3D chromatin structure to drive oncogenic transcription, with implications for tumor cell identity and therapy.
N. Jung, V. Lopez-Pajares, L. Donohue et al.· Science Advances· 0 citations
