Mitochondrial DHODH regulates hypoxia-inducible factor 1 expression in OTSCC

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Oral tongue squamous cell carcinoma (OTSCC) is characterized by hypoxia and poor prognosis.
• Hypoxia-inducible factor-1 (HIF-1) signaling is linked to OTSCC progression, metastasis, and adverse outcomes.
• Dihydroorotate dehydrogenase (DHODH) is crucial for pyrimidine biosynthesis and its role in OTSCC remains unclear.

Purpose of the Study:

• To investigate the biological function of DHODH in OTSCC.
• To determine if DHODH regulates HIF-1 signaling in OTSCC.
• To explore DHODH as a potential therapeutic target for OTSCC.

Main Methods:

• Assessed DHODH function using proliferation, migration, and anoikis resistance assays.
• Utilized Western blot and luciferase activity assays to examine DHODH's regulation of HIF-1.
• Analyzed The Cancer Genome Atlas (TCGA) data for DHODH expression in head and neck cancers.

Main Results:

• Increased DHODH expression correlates with advanced tumor stage and poor differentiation in head and neck cancers.
• DHODH enhances OTSCC proliferation, aggressiveness, tumor growth, and metastasis in vivo.
• DHODH upregulates HIF1A transcription, stability, and transactivation, mediated by reactive oxygen species (ROS) production.

Conclusions:

• DHODH promotes OTSCC progression and metastasis by activating HIF-1 signaling through ROS generation.
• Inhibiting DHODH reduces ROS production and HIF-1A upregulation, suppressing tumor growth.
• The DHODH inhibitor atovaquone presents a potential novel therapeutic strategy for OTSCC.