USP39 deubiquitinase: Dual roles in RNA splicing and protein stabilization in cancer therapeutics

Ubiquitin-specific protease 39 (USP39) is a multifunctional protein that plays a pivotal role in cellular homeostasis and tumorigenesis by integrating ubiquitin-dependent regulation, a mechanism governing protein stability, function, and interactions via the ubiquitination system, with RNA splicing. Although categorized within the deubiquitinating enzyme (DUB) USP family, USP39 exhibits markedly reduced canonical enzymatic activity due to structural alterations in its conserved cysteine-histidine catalytic motif. Instead, it engages in biological processes through non-catalytic mechanisms, such as zinc finger domain-mediated spliceosome assembly and non-classical deubiquitination to stabilize oncoproteins. As a key regulator of pre-mRNA splicing, the cell cycle (particularly the G2/M transition), and tumorigenesis, USP39 dysregulation is closely associated with cancer proliferation, metastasis, and chemoresistance. Emerging research on USP39's dual roles in deubiquitination and RNA splicing regulation has established it as a central hub molecule in cancer biology. This article systematically reviews the structural uniqueness, dual regulatory functions, and pathological implications of USP39, highlighting its potential as both a biomarker and therapeutic target. These insights aim to inform the development of novel strategies for tumor diagnosis and treatment.