Curcumin suppresses HNSCC tumorigenesis through directly targeting FOSL1/JUN

Area of Science:

• Oncology
• Natural Products Chemistry
• Molecular Biology

Background:

• Natural products offer alternatives for cancer therapy, especially for underserved patients.
• Curcumin, from turmeric, exhibits anti-cancer potential, but its mechanism in head and neck squamous cell carcinoma (HNSCC) is unclear.

Purpose of the Study:

• To investigate curcumin's efficacy and molecular mechanism as an inhibitor of HNSCC tumorigenesis.
• To identify curcumin's direct molecular targets in HNSCC.

Main Methods:

• Comparative analysis of natural products (curcumin, gingerol, allicin) against HNSCC.
• Transcriptomic and Gene Set Enrichment Analyses to identify signaling pathways affected by curcumin.
• Biophysical assays, biochemical assays, and chromatin immunoprecipitation to determine curcumin's molecular target and DNA-binding disruption.
• In vivo xenograft studies to evaluate curcumin's anti-tumor efficacy and toxicity.

Main Results:

• Curcumin potently inhibited HNSCC cell proliferation, invasion, and cancer stem cell self-renewal, comparable to cisplatin.
• Curcumin significantly suppressed FOSL1/AP-1 signaling, a key oncogenic pathway in HNSCC.
• Curcumin directly binds to the FOSL1/JUN heterodimer, disrupting its DNA-binding activity and inhibiting recruitment to oncogenic gene promoters (BMI1, MET, EGFR, TP63).
• Curcumin suppressed HNSCC tumor growth in vivo with superior efficacy to a FOSL1/AP-1 inhibitor (T-5224) and without apparent toxicity.

Conclusions:

• Curcumin directly targets the FOSL1/JUN complex, representing a novel mechanism for suppressing HNSCC.
• Curcumin demonstrates significant anti-tumor activity and a favorable safety profile, supporting its potential as an affordable and safe therapeutic agent for HNSCC.