ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• BRAF-mutant melanoma cells develop resistance to RAF inhibitors.
• ERK signaling pathway inhibition induces stemness transcription factor FOXD3, mediating adaptive resistance.
• The precise mechanism of ERK signaling control over FOXD3 expression was previously unknown.

Purpose of the Study:

• To elucidate the mechanism by which ERK signaling controls FOXD3 expression in BRAF-mutant melanoma.
• To identify key transcription factors involved in RAF inhibitor resistance.
• To explore potential therapeutic strategies targeting resistance pathways.

Main Methods:

• Investigated the role of SOX10 in regulating FOXD3 expression using mutant BRAF melanoma cell lines.
• Utilized techniques such as promoter binding assays and Western blotting to analyze protein interactions and modifications.
• Performed in vitro and in vivo experiments involving SOX10 depletion to assess its impact on drug sensitivity.

Main Results:

• SOX10 was identified as essential and sufficient for RAF inhibitor-induced FOXD3 expression in BRAF-mutant melanoma.
• SOX10 directly activates FOXD3 transcription by binding to its promoter.
• ERK-mediated phosphorylation of SOX10 inhibits its transcriptional activity by interfering with sumoylation at K55.
• Depletion of SOX10 sensitized melanoma cells to RAF inhibitors both in vitro and in vivo.

Conclusions:

• Discovered a novel phosphorylation-dependent regulatory mechanism for SOX10 transcription activity.
• Established an ERK1/2/SOX10/FOXD3/ERBB3 signaling axis responsible for adaptive resistance to RAF inhibitors in BRAF-mutant melanoma.
• SOX10 represents a potential therapeutic target to overcome RAF inhibitor resistance in melanoma.