SPOP, also known as Speckle-type POZ protein, is a substrate-binding adaptor of the CULLIN3/RING-box1 E3 ubiquitin ligase complex. It plays a crucial role in ubiquitin-mediated protein degradation, which is essential for regulating proper cellular function. SPOP is involved in multiple biological pathways such as androgen/AR signaling, DNA repair and methylation, cellular stress surveillance, cancer metabolism, and immunity [1,3]. Its dysregulation is associated with the development and progression of various cancers [1,3,6]. Genetic models, like KO/CKO mouse models, are valuable for studying its functions in vivo.

In prostate cancer, cytoplasmic SPOP binds and non-degradatively ubiquitinates p62 at residue K420, suppressing p62-dependent autophagy. PCa-associated SPOP mutants lose this capacity and instead promote autophagy and the redox response in a dominant-negative manner [2]. In endometrial cancer, wild-type SPOP binds to IRF1 and triggers its ubiquitin-proteasomal degradation to suppress PD-L1 expression, while EC-associated SPOP mutants stabilize IRF1 and upregulate PD-L1, promoting tumor immune escape [4]. In prostate cancer, SPOP mutations are associated with upregulation of a 29-gene noncanonical STING signature, and PARP inhibitor treatment can shift the signaling from immunosuppressive to antitumor in SPOP-mutant castrate-resistant prostate cancer [5].

In conclusion, SPOP is essential for ubiquitin-mediated protein degradation and is involved in multiple cancer-relevant pathways. Model-based research, especially through KO/CKO mouse models, has revealed its significant roles in prostate and endometrial cancers, providing insights into the molecular mechanisms of cancer development and potential therapeutic strategies.