Novel insights into the SPOP E3 ubiquitin ligase: From the regulation of molecular mechanisms to tumorigenesis

• Published in: Biomedicine & pharmacotherapy 2022-05, Vol.149, p.112882-112882, Article 112882
• Main Authors: Li, Xian-Miao, Wu, Huan-Lei, Xia, Qi-Dong, Zhou, Peng, Wang, Shao-Gang, Yu, Xiao, Hu, Jia
• Format: Article
• Language: English
• Subjects: Biological function; Cancer therapy; Carcinogenesis - metabolism; Cell Transformation, Neoplastic; Cullin Proteins - metabolism; Humans; Nuclear Proteins - metabolism; Oncogenesis; Repressor Proteins - metabolism; SPOP; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2022.112882

Ubiquitin-mediated protein degradation is the primary biological process by which protein abundance is regulated and protein homeostasis is maintained in eukaryotic cells. Speckle-type pox virus and zinc finger (POZ) protein (SPOP) is a typical substrate adaptor of the Cullin 3-RING ligase (CRL3) family; it serves as a bridge between the Cullin 3 (Cul3) scaffold protein and its substrates. In recent years, SPOP has received increasing attention because of its versatility in its regulatory pathways and the diversity of tumor types involved. Mechanistically, SPOP substrates are involved in a wide range of biological processes, and abnormalities in SPOP function perturb downstream biological processes and promote tumorigenesis. Additionally, liquid-liquid phase separation (LLPS), a potential mechanism of membraneless organelle formation, was recently found to mediate the self-triggered colocalization of substrates with higher-order oligomers of SPOP. Herein, we summarize the structure of SPOP and the specific mechanisms by which it mediates the efficient ubiquitination of substrates. Additionally, we review the biological functions of SPOP, the regulation of SPOP expression, the role of SPOP in tumorigenesis and its therapeutic value. [Display omitted] •SPOP is involved in regulating a range of downstream substrates and their functions.•SPOP displays dual roles to promote or inhibit tumorigenesis in a tumor-context dependent manner.•A variety of upstream signal transduction pathways participate in modulating the activation of SPOP protein in carcinogenesis.•SPOP-related anticancer therapy is promising but needs further validation.