Bidirectional regulation of the ubiquitin-RNA modification axis in cancer.

RNA modifications, dynamically regulated by RNA-modifying proteins (RMPs) acting as "writers", "erasers", and "readers", play pivotal roles in governing gene expression and cellular fate. These modifications are also intimately linked to cancer initiation and progression. Dysregulation of RMPs in tumors disrupts RNA modification homeostasis, thereby promoting cancer progression through enhanced proliferation, metastasis, and immune evasion. The ubiquitination system serves as critical regulator of RMP stability and activity, which in turn shapes the cancer epitranscriptome. Conversely, RNA modifications feedback into ubiquitination pathways by modulating the stability and translation of mRNAs encoding ubiquitination-related factors. This bidirectional crosstalk between RMPs and ubiquitination forms a sophisticated regulatory network that enhances cancer adaptability. Notably, emerging therapeutic strategies aimed at targeting RMP ubiquitination have shown promising potential. In this review, we systematically examine the bidirectional regulatory axis between ubiquitination and RMPs in cancer pathogenesis. We first outline how ubiquitination controls RMP activity and the consequent epitranscriptomic alterations and then explore how RNA modifications reciprocally influence ubiquitination pathways. Building on this mechanistic foundation, we evaluate current therapeutic approaches targeting the ubiquitination-epitranscriptome axis and highlight key knowledge gaps in our understanding of this dynamic regulatory network. Finally, we propose future research directions to fully decode the therapeutic potential of this dynamic regulatory network in oncology, thereby providing novel perspectives on cancer development.