Nuclear TOP1MT Confers Cisplatin Resistance via Pseudogene in HNSCC

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Cisplatin resistance significantly limits treatment efficacy in head and neck squamous cell carcinoma (HNSCC).
• Understanding the molecular mechanisms underlying cisplatin resistance is crucial for developing novel therapeutic strategies.

Purpose of the Study:

• To identify key molecular players and pathways involved in cisplatin resistance in HNSCC.
• To elucidate the role of mitochondrial topoisomerase I (TOP1MT) in conferring cisplatin resistance.

Main Methods:

• Quantitative proteomics to identify differential proteins.
• Laser confocal microscopy and nucleocytoplasmic separation assays for protein localization.
• Chromatin immunoprecipitation sequencing, dual-luciferase reporter assays, and RNA immunoprecipitation to investigate molecular interactions.
• In vivo and in vitro experiments in HNSCC models.

Main Results:

• TOP1MT was identified as a critical driver of cisplatin resistance in HNSCC.
• TOP1MT translocated to the nucleus (nTOP1MT) in cisplatin-resistant cells.
• nTOP1MT transcriptionally activated the pseudogene MTATP6P1, which acted as a competing endogenous RNA (ceRNA) for miR-137 and miR-491-5p.
• This ceRNA mechanism increased MTATP6 expression, enhancing mitochondrial oxidative phosphorylation (OXPHOS) and promoting cisplatin resistance.

Conclusions:

• Nuclear TOP1MT activates MTATP6P1, leading to increased MTATP6 expression via a ceRNA network.
• Enhanced OXPHOS contributes to cisplatin resistance in HNSCC.
• This study reveals a novel mechanism for cisplatin resistance and identifies nTOP1MT as a potential therapeutic target.