The AP-1 transcription factor FOSL1 causes melanocyte reprogramming and transformation.

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• The MAPK pathway is frequently activated in melanoma, driving cancer progression.
• Constitutive expression of immediate early genes, like AP-1 family members, occurs under pathological conditions.
• The role of permanent immediate early gene expression in melanoma remains largely unknown.

Purpose of the Study:

• To investigate the role of FOSL1, a key AP-1 member, in melanoma.
• To determine the oncogenic potential of FOSL1 in melanocytes.
• To elucidate the molecular mechanisms underlying FOSL1-mediated melanocyte transformation.

Main Methods:

• Analysis of FOSL1 expression in melanoma cells and patient samples.
• Functional studies of FOSL1 in melanoma cell migration, proliferation, and anoikis-independent growth.
• In vivo studies assessing the tumor-forming capacity of FOSL1-expressing melanocytes.
• Investigation of FOSL1-induced changes in gene expression, including MITF, AXL, MYC, E2F3, and AP-1.

Main Results:

• FOSL1 is the primary immediate early AP-1 member induced by melanoma oncogenes.
• FOSL1 promotes melanoma cell migration, proliferation, and anoikis-independent growth via HMGA1.
• Enhanced FOSL1 expression transforms melanocytes, causing subcutaneous tumor growth in vivo.
• FOSL1 downregulates MITF and upregulates AXL, shifting the MITF/AXL balance, and reinforces pro-tumorigenic transcription factors.

Conclusions:

• FOSL1 is a potent oncogene in melanoma, driving tumor progression and transformation.
• FOSL1 acts as a novel reprogramming factor for melanocytes, with significant tumor transformation potential.
• The FOSL1-mediated reprogramming involves downregulation of MITF, upregulation of AXL, and reinforcement of pro-tumorigenic transcription factors, promoting key growth processes.