DDX5: A Versatile RNA Helicase in Cancer and Cell Fate Determination—Linking c-Myc and JAK2 V617F Signaling to Emerging Therapeutics

Traditionally regarded as a DEAD-box RNA helicase involved in RNA metabolism, DDX5 (also known as p68) has emerged as a signal-responsive regulator that integrates RNA processing with transcriptional control, thereby influencing cell fate determination and tumorigenesis. Beyond its canonical roles in pre-mRNA splicing, ribosome biogenesis, microRNA maturation, and R-loop resolution, DDX5 also functions in a helicase-independent manner as a transcriptional co-activator for diverse transcription factors and signaling pathways. Recent studies have revealed a dichotomy in which the RNA helicase activity and scaffolding/co-activator functions of DDX5 are selectively deployed in a context-dependent manner. In cancer, DDX5 enhances the transcriptional activity and transforming capacity of the proto-oncogene c-Myc and is itself transcriptionally induced by c-Myc, forming a positive feedback loop that sustains oncogenic transcriptional programs. DDX5 is also indispensable for transformation driven by the constitutively active JAK2 V617F mutant, a major driver of myeloproliferative neoplasms, where it promotes malignant signaling largely independently of its RNA helicase activity. In contrast, during adipocyte differentiation, the helicase function of DDX5 is essential for glucocorticoid receptor transcriptional programs. Importantly, recent studies have identified the small-molecule compound FL118 as a potent DDX5 degrader, providing proof of concept that targeting DDX5 protein stability represents a promising therapeutic strategy.