ATXN3, the product of the ATXN3 gene, is a ubiquitin hydrolase (deubiquitinase, DUB) ubiquitously expressed in various cell types, including peripheral and neuronal tissues. It is involved in multiple cellular pathways such as proteostasis, DNA repair, transcriptional regulation, and chromatin structure regulation [2,3]. Expansion of CAG trinucleotides within the ATXN3 gene leads to an expanded polyglutamine domain in the encoded protein, associated with spinocerebellar ataxia type 3 (also known as Machado-Joseph disease), the most common dominantly inherited ataxia worldwide [2,6].

Targeted deletion of ATXN3 in cancer cells largely abolished IFN-γ-and hypoxia-induced PD-L1 expression and enhanced antitumor immunity in mice, and these effects were partially reversed by PD-L1 reconstitution. Tumoral ATXN3 suppression also improved the preclinical efficacy of checkpoint blockade antitumor immunotherapy [1]. In prostate cancer, depletion of ATXN3 decreased cell proliferation, invasion, and stem-like properties, with effects rescued by YAP overexpression [4]. In contrast, in colon adenocarcinoma, CRISPR-mediated ATXN3 deletion intensified cancer growth, while ectopic expression of Galectin-9 reversed the growth of ATXN3-null colon cancer in mice [5].

In conclusion, ATXN3 is a multifunctional protein with roles in proteostasis, DNA repair, and transcriptional regulation. Its functions are context-dependent, acting as a positive regulator of PD-L1 transcription in tumor immune evasion, promoting prostate cancer progression, yet suppressing colon cancer growth. Gene knockout models in mice have been crucial in revealing these functions in cancer-related processes, enhancing our understanding of disease mechanisms and potential therapeutic targets.