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P63 and its co-binding factor Znf148 cooperate to control squamous cell carcinoma proliferation

ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) are common and aggressive malignancies, and little progress has been made in improving outcomes for patients. HNSCC exhibit frequent overexpression of the p53-related transcription factor TP63. Here, we show that ZNF148 is an important partner in p63-driven tumorigenesis. Mechanistically, while ZNF148 alone binds CCND1 gene promoter, the p63-ZNF148 complex co-binds a CCND1 upstream enhancer leading to an enhancer-derived RNAs (eRNA3) acting as cis-regulatory elements for CCND1 transcription. The eRNA3 p63/ZNF148-dependent transcription is required to support high-rate proliferation in HNSCC. Interestingly, p63/ZNF148, eRNA3 and cyclin D1 expression is highly co-correlated in primary HNSCC, including laryngeal squamous cell carcinoma (LSCC). Their co-expression correlated to tumor stage and lymph nodes positivity. These results revealed a strong cooperation of the two transcription factors, p63 and ZNF148, as HNSCC oncogenic drivers. Altogether, these findings provide a framework to facilitate categorization of HNSCC sub-types, prognostic/diagnostic biomarkers, and a foundation for development of new therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239709 | GEO | 2025/07/02

REPOSITORIES: GEO

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

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