p63 and its co-binding factor Znf148 cooperate to control squamous cell carcinoma proliferation

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.