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

• 成果类型: Article
• 署名作者: Pecorari, Rosalba; Mancini, Mara; Smirnov, Artem; Corleone, Giacomo; Novelli, Flavia; Lena, Anna Maria; Canonico, Mariacristina Franzese; Montanaro, Manuela; Cappello, Angela; Sacconi, Andrea; Misso, Gabriella; Falco, Michela; Tammaro, Chiara; Ciccosanti, Fabiola; Piacentini, Mauro; Scimeca, Manuel; Caraglia, Michele; Blandino, Giovanni; Mauriello, Alessandro; Fanciulli, Maurizio; Melino, Gerry; Candi, Eleonora
• 署名单位: IRCCS Istituto Dermopatico dell'Immacolata (IDI); University of Rome Tor Vergata; University of Hawaii System; Cancer Research Center of Hawaii; Universita della Campania Vanvitelli
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12893
• DOI: 10.1073/pnas.2500579122
• 发表日期: 2025-07-07
• 关键词: transcription factor zbp-89; nf-kappa-b; vimentin gene; regenerative proliferation; epithelial development; stem-cells; expression; enhancers; protein; p53

摘要

Head and neck squamous cell carcinoma (HNSCC) is a common and aggressive malignancy. While significant advances have been made in the management of low-grade cancer, treatment of advanced HNSCC remains challenging. Here, we used a proteomic approach to find binding partners of the oncogene p63, the most frequently amplified transcription factor in HNSCC. We identified a zinc finger protein, ZNF148, which is coexpressed and physically binds p63 in carcinoma cells. Genome occupancy analyses identified a functional transcribed enhancer-derived RNA (eRNA) upstream of the CCND1 gene occupied by both factors. Mechanistically, p63 and ZNF148 control transcription of this eRNA, leading to overexpression of cyclin D1 to reinforce tumor cell proliferation. Importantly, this axis is specific for cancer cells and remains inactive in normal epithelial cells. The expression levels of these factors and the eRNA are positively correlated in cancer and associated with advanced stage and metastasis. Collectively, our data reveal a molecular pathway controlling HNSCC progression and identify potential selective targets for cancer treatment.