SPOP-dependent destabilization of SYT12 in a GSK-3β-dependent manner in papillary thyroid cancer cells.

Synaptotagmin 12 (SYT12), a protein found to be upregulated in papillary thyroid cancer (PTC), has emerged as a potential biomarker for this malignancy. However, the mechanisms governing its expression remain poorly understood. In this study, we identify SYT12 as a novel substrate of SPOP, an adaptor of the Cullin 3 E3 ubiquitin ligase complex. SPOP binds to SYT12 and mediates SYT12's K48-linked polyubiquitination and subsequent proteasomal degradation. This interaction is dependent on the degron motif within SYT12, and deletion or mutation of the degron significantly impairs SPOP binding and stabilizes SYT12. We further demonstrate that GSK-3β-mediated phosphorylation of the degron is essential for SPOP recognition. Pharmacological inhibition of GSK-3β disrupts the SPOP-SYT12 interaction and increases SYT12 protein levels. Functionally, the SPOP-SYT12 axis modulates PTC cell viability and proliferation. Collectively, these findings uncover a novel regulatory mechanism of SYT12 expression and suggest that targeting the SPOP-SYT12 pathway may represent a promising therapeutic strategy for PTC.