Epigenetic and post-transcriptional integration of lncRNAs and EZH2 in GI tumorigenesis

Gastrointestinal (GI) cancers, more broadly, colorectal, gastric, pancreatic, and esophageal malignancies, remain major contributors to global cancer mortality, driven by late diagnosis, metastasis, and resistance to therapy. Increasing evidence highlights the enhancer of zeste homolog 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), as a central epigenetic driver of GI tumorigenesis through deposition of H3K27me3 and silencing of tumour-suppressor genes. However, the oncogenic functions of EZH2 are not autonomous; long non-coding RNAs (lncRNAs) critically shape its locus specificity, chromatin recruitment, stability, and integration into broader transcriptional programs. Numerous lncRNAs in GI cancers, such as LINC00337, LINC00673, ZFAS1, MSTO2P, and HOXA-AS2, recruit EZH2 to repress key regulators of the cell cycle and differentiation. Other lncRNAs act through ceRNA mechanisms to de-repress EZH2 expression, or engage EZH2 within oncogenic signalling pathways including AKT, STAT3, Notch, and Wnt/β-catenin. These interactions contribute to malignant proliferation, invasion, metastasis, cancer stemness, and therapeutic resistance. Despite intense investigation, mechanistic ambiguity remains due to limitations in distinguishing direct EZH2 recruitment from correlative chromatin association, and in validating ceRNA activity within physiologic stoichiometric constraints. Nevertheless, the lncRNA-EZH2 axis presents a promising therapeutic avenue, with RNA-based strategies offering the potential to disrupt pathological lncRNA-EZH2 assemblies with greater precision than catalytic EZH2 inhibitors alone. This review synthesizes current mechanistic and functional insights into lncRNA-EZH2 regulation in GI cancers, organizing these interactions into key biological modules and highlighting emerging opportunities for diagnostic and therapeutic development.