The interplay between post-transcriptional RNA regulation and Wnt/β-Catenin signaling in cancer: A Review

The Wnt/β-Catenin signaling pathway, a well-established driver of tumorigenesis, functions primarily through β-Catenin-mediated transcriptional activation, which is a process driven by multi-protein signal cascades. Emerging evidence reveals its increasing role in post-transcriptional regulation, including RNA splicing, stability, and epitranscriptomic modifications. Notably, mRNAs encoding key Wnt signaling regulators are themselves subjected to context-dependent post-transcriptional fine-tuning, establishing a bidirectional regulatory network that amplifies Wnt-driven oncogenic signaling. Despite the biological significance of this multi-layered regulation, its systematic elucidation remains incomplete. This review synthesizes recent advances in understanding the crosstalk between Wnt/β-Catenin signaling and post-transcriptional RNA homeostasis, with a focused analysis of the splicing, stability, and m6A modification of mRNA. Importantly, we propose a novel mechanistic framework wherein the Wnt/β-Catenin signaling contributes significantly to oncogenesis through multidimensional control of RNA metabolism, extending beyond its canonical transcriptional regulatory role. Our analysis highlights the therapeutic potential of targeting post-transcriptional regulatory nodes (e.g., spliceosome components, RNA-binding proteins, m6A-modifying enzymes) to disrupt oncogenic RNA homeostasis. This synthesis provides a rationale for developing combination strategies that integrate Wnt pathway inhibition with targeting of RNA processing modulators, offering a broader perspective on modulating Wnt signaling and cancer treatment.