Abstract 4331: Collaboration between p63 and ZNF148 in regulating squamous cell carcinoma progression

Abstract p63, a member of the p53 family of transcription factors, is essential for the development and maintenance of squamous epithelium. In squamous cell carcinomas, including head and neck squamous cell carcinoma (HNSCC), p63 is the most frequently amplified transcription factor at the genomic level and is often overexpressed. HNSCC is a prevalent and aggressive form of cancer and treating advanced stages of the disease remains a significant challenge. Using a proteomics-based approach, we identified new binding partners of the oncogenic variant DNp63. Among these, the zinc finger protein ZNF148 was found to be co-expressed with DNp63 and to physically interact with it in carcinoma cells. Genome-wide binding studies revealed a functional enhancer-derived RNA (eRNA) located upstream of the CCND1 gene, which is bound by both DNp63 and ZNF148. This interaction regulates the transcription of the eRNA, leading to increased cyclin D1 expression, thereby promoting tumor cell proliferation. Notably, this pathway is specific to cancer cells and remains inactive in normal epithelial cells. The expression levels of DNp63, ZNF148, and the eRNA are positively correlated in cancer, with higher levels linked to advanced disease and metastasis. Furthermore, ZNF148 also independently influences cell migration and inflammatory responses in HNSCC by regulating genes involved in actin cytoskeleton remodeling and type I and II interferon signaling pathways. Together, these findings uncover a novel molecular mechanism driving HNSCC progression and highlight potential targets for selective cancer therapies. Citation Format: Artem Smirnov, Eleonora Candi. Collaboration between p63 and ZNF148 in regulating squamous cell carcinoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4331.