Mapping of the hSOX10 Proximal Protein Interactome in Human Melanoma.

The transcription factor SOX10 is a central regulator of melanoma, influencing tumor initiation, progression, phenotypic plasticity, and therapeutic resistance, yet the protein-protein interactions underlying its function remain poorly defined. To address this, we conducted the first dedicated, comprehensive mapping of the human SOX10 (hSOX10) proximal protein interactome using miniTurbo (mT) proximity-dependent biotinylation coupled with mass spectrometry in A375 melanoma cells. Stable lines expressing N- or C-terminal mT-tagged hSOX10 fusion proteins at near-endogenous levels enabled the unbiased capture of proximal proteins in a native cellular context, identifying 847 melanoma-enriched candidate hSOX10 interactors. Stringent statistical filtering, contaminant frequency profiling, and subcellular localization context refined this to 180 high-confidence candidates, including known hSOX10 partners and previously unidentified candidates. Integration of orthogonal biological relevance criteria (functional enrichment and network context, transcriptomic coexpression with hSOX10, and genomic co-occurrence in melanoma) further refined the dataset to 124 biologically relevant candidates enriched for transcriptional regulators, cofactors, chromatin-modifying complexes, and associated pathways. These proteins were stratified using an evidence-based prioritization framework incorporating transcriptomic, genomic, and chromatin-based context without additional exclusion. Collectively, this work provides a high-confidence resource for the hSOX10 proximal protein interactome in melanoma and a framework for generating testable hypotheses regarding hSOX10-associated regulatory networks, melanoma biology, and therapeutic vulnerabilities.