Speckle-type POZ protein (SPOP) is a substrate-binding adaptor of the CULLIN3/RING-box1 E3 ubiquitin ligase complex [1]. 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].

In prostate and endometrial cancers, SPOP is frequently mutated, while it is overexpressed in renal cell carcinoma (RCC) [1]. 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 [2]. Also, in prostate cancer, SPOP-mediated ubiquitination and degradation of PDK1 suppress AKT kinase activity and oncogenic functions, but SPOP mutations impair PDK1 degradation and activate the AKT kinase, leading to tumor malignancies [3]. In endometrial cancer, wild-type SPOP negatively regulates PD-L1 expression by degrading IRF1, a transcription factor for PD-L1, while EC-associated SPOP mutants stabilize IRF1 and upregulate PD-L1, promoting tumor immune escape [4].

In conclusion, SPOP is a key regulator in multiple biological pathways through its role in ubiquitin-mediated protein degradation. Its mutations in prostate and endometrial cancers, and overexpression in RCC, significantly impact cancer-relevant pathways. The study of SPOP in KO/CKO mouse models, as shown in the references, helps to reveal its role in tumorigenesis and immune escape, providing potential targets for cancer treatment.