HaloPROTAC-mediated degradation reveals SOX10-dependent gene expression changes in melanoma cells

The transcription factor SOX10 is required for melanoma cell proliferation. However, SOX10 expression in single cells is heterogeneous, and low SOX10-expressing melanoma cells exhibit a dormant-invasive phenotype associated with drug resistance and metastasis. Despite longstanding interest in SOX10 as a diagnostic marker and potential therapeutic target in melanoma, the function and targets of SOX10 remain incompletely understood. New tools for the study of SOX10 are needed to address these gaps in our knowledge. In this study, we engineered a patient-derived WW165 melanoma cell line for programmable SOX10 targeted proteolysis. We achieved this by replacing the endogenous copies of SOX10 with a SOX10-HaloTag transgene that supports cell growth, but can be rapidly degraded by the ubiquitin-proteasome system upon with a commercially available HaloPROTAC3 degrader molecule. We demonstrate that inducible degradation of SOX10-HaloTag faithfully recapitulates the known SOX10 transcriptional program, while also enabling discovery of NAV2 and NCKAP5 as novel SOX10 target genes. This study demonstrates that new biological insights into the function of SOX10 can be enabled by targeted degradation.