p63 and ZNF148 cooperate to regulate head and neck squamous cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with challenging treatments for advanced stages.
• The oncogene p63, a frequently amplified transcription factor, plays a crucial role in HNSCC pathogenesis.
• Understanding p63's interactions is key to developing targeted therapies for HNSCC.

Purpose of the Study:

• To identify binding partners of the oncogene p63 in HNSCC using a proteomic approach.
• To elucidate the molecular mechanisms by which p63 contributes to HNSCC progression.
• To discover potential therapeutic targets for advanced HNSCC.

Main Methods:

• Proteomic analysis to identify p63 binding partners.
• Co-immunoprecipitation and Western blotting to confirm protein interactions.
• Genome occupancy analyses (e.g., ChIP-seq) to map binding sites.
• RNA sequencing and quantitative PCR to assess gene and eRNA expression levels.

Main Results:

• Identified ZNF148 as a p63 binding partner coexpressed in HNSCC cells.
• Discovered a functional enhancer-derived RNA (eRNA) upstream of the CCND1 gene occupied by p63 and ZNF148.
• Demonstrated that p63 and ZNF148 control eRNA transcription, leading to CCND1 overexpression and promoting tumor cell proliferation.
• Confirmed this axis is specific to cancer cells and inactive in normal epithelium.
• Found positive correlations between expression levels of p63, ZNF148, the eRNA, and advanced HNSCC stage and metastasis.

Conclusions:

• A novel molecular pathway involving p63, ZNF148, and a CCND1-regulating eRNA drives HNSCC progression.
• This pathway is cancer-specific, highlighting its potential as a selective therapeutic target.
• Targeting this axis could offer new treatment strategies for advanced HNSCC and metastatic disease.