The Splicing Factor PTBP1 Represses TP63 γ Isoform Production in Squamous Cell Carcinoma

Area of Science:

• Molecular Biology
• Cancer Biology
• Genetics

Background:

• The TP63 gene produces the p63 transcription factor, crucial in squamous cell carcinomas.
• Alternative splicing generates multiple p63 isoforms (α, β, γ, δ) with distinct regulatory functions.
• The TP63γ isoform promotes epithelial-to-mesenchymal transition (EMT), contrasting with the α isoform's inhibitory role.

Purpose of the Study:

• To identify the prognostic significance of the TP63γ isoform in head and neck squamous cell carcinoma (HNSCC).
• To investigate the regulatory mechanisms controlling TP63γ isoform production.
• To identify potential therapeutic targets for modulating TP63γ expression.

Main Methods:

• Analysis of The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data.
• RNA immunoprecipitation (RIP) and in vitro interaction assays.
• Splice reporter minigene assays in cell lines and Xenopus embryos.

Main Results:

• Increased TP63γ isoform proportion correlates with poor survival and desmosomal gene downregulation in HNSCC patients.
• PTBP1 expression is inversely correlated with TP63γ abundance across multiple tissues.
• PTBP1 depletion increases TP63γ levels; PTBP1 directly binds TP63 pre-mRNA near the γ-specific exon.

Conclusions:

• TP63γ serves as an unfavorable prognostic marker in HNSCC.
• PTBP1 is identified as the first direct splicing regulator of TP63γ production.
• PTBP1 represents a potential therapeutic target for controlling TP63 isoform expression.