It takes two to tango: the intersection of deubiquitinases and m6A modification in cancer.

The dynamic and reversible N6-methyladenosine (m6A) RNA modification has emerged as a pivotal layer of epitranscriptomic regulation in cancer, governing RNA metabolism and function. Concurrently, deubiquitylating enzymes (DUBs), key components of the post-translational modifications (PTMs) system, orchestrate protein stability and signaling pathways crucial for tumorigenesis. Recent evidence reveals extensive and intricate crosstalk between these two regulatory systems, forming a complex network that can influence cancer progression. This review systematically explores the bidirectional interplay between DUBs and m6A modification. On one hand, specific DUBs can deubiquitinate and stabilize core m6A "writers" (methyltransferases), "erasers" (demethylases), or "readers" (recognition proteins), thereby influencing RNA metabolism and downstream gene expression. On the other hand, m6A modification can regulate the expression of certain DUBs, either by influencing the stability and translation of their mRNAs or by controlling associated regulatory factors. This reciprocal regulation profoundly impacts key oncogenic processes, including cell proliferation, metastasis, metabolic reprogramming, and therapy resistance. By integrating current findings, this review highlights the significance of the DUB-m6A axis as a critical regulatory hub in cancer biology. Deciphering this crosstalk not only provides novel insights into tumor mechanisms but also unveils promising therapeutic targets for overcoming drug resistance and developing innovative anti-cancer strategies.