HaloPROTAC-mediated degradation reveals SOX10-dependent gene expression changes in melanoma cells
- 1Yale University
Abstract
The transcription factor SOX10 is required for melanoma cell proliferation. However, SOX10 expression in single cells is heterogeneous, and low SOX10-expressing 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 molecular mechanism and targets of SOX10 remain incompletely understood. New tools for the study and perturbation of SOX10 in cancer-relevant systems 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 SOX10 target genes previously undetected with standard genetic silencing approaches. We validated NAV2 and NCKAP5 as novel genes that are directly bound by SOX10 and coregulated with SOX10 expression in a patient cohort. This study demonstrates that new biological insights into the function of SOX10 can be enabled by targeted degradation and suggests that analogous approaches could prove powerful in the study of other transcription factors. We further suggest that the SOX10-HaloTag expressing melanoma cell line developed in this study could find further applications in investigating the consequences of SOX10 targeted degradation in vitro and in vivo.
Related
- Intercellular Transfer of CD155 Mediated by Melanoma Extracellular Vesicles Downregulates DNAM-1 Expression on NK Cells.
- HDAC inhibition drives NOX5-dependent oxidative stress and sensitizes uveal melanoma cells to SOD1 inhibition
- Beyond Dmax and DC50: A simple tool to evaluate the complex PROTAC-mediated kinetic degradation dynamics
- Mesenchymal stem cell-derived exosomes alleviate renal interstitial fibrosis via pVHL-mediated HIF-1α ubiquitination and degradation
- Low-valine diet ameliorates pathological cardiac hypertrophy by inhibiting LONP1-mediated degradation of ATP5F1B in male rodents
BibTeX
@misc{purvis2026haloprotacmediated,
title = {{HaloPROTAC-mediated degradation reveals SOX10-dependent gene expression changes in melanoma cells}},
author = {A. L. Purvis and C. M. DeRosa and A. P. Pintado-Urbanc and K. Agnish and K. Jiang and A. Bacchiocchi and R. Halaban and S. A. Slavoff},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.19.760213},
url = {https://www.biorxiv.org/content/10.64898/2026.10.19.760213v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - HaloPROTAC-mediated degradation reveals SOX10-dependent gene expression changes in melanoma cells
AU - A. L. Purvis
AU - C. M. DeRosa
AU - A. P. Pintado-Urbanc
AU - K. Agnish
AU - K. Jiang
AU - A. Bacchiocchi
AU - R. Halaban
AU - S. A. Slavoff
PY - 2026
DA - 2026/10/19
PB - bioRxiv
DO - 10.64898/2026.10.19.760213
UR - https://www.biorxiv.org/content/10.64898/2026.10.19.760213v1
AB - The transcription factor SOX10 is required for melanoma cell proliferation. However, SOX10 expression in single cells is heterogeneous, and low SOX10-expressing 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 molecular mechanism and targets of SOX10 remain incompletely understood. New tools for the study and perturbation of SOX10 in cancer-relevant systems 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 SOX10 target genes previously undetected with standard genetic silencing approaches. We validated NAV2 and NCKAP5 as novel genes that are directly bound by SOX10 and coregulated with SOX10 expression in a patient cohort. This study demonstrates that new biological insights into the function of SOX10 can be enabled by targeted degradation and suggests that analogous approaches could prove powerful in the study of other transcription factors. We further suggest that the SOX10-HaloTag expressing melanoma cell line developed in this study could find further applications in investigating the consequences of SOX10 targeted degradation in vitro and in vivo.
SN - 2692-8205
ER -