p63 and ZNF148 cooperate to regulate head and neck squamous cell carcinoma
Menée à l'aide de lignées cellulaires et d'échantillons biopsiques prélevés sur des patients atteints d'un carcinome épidermoïde de la tête et du cou, cette étude met en évidence un mécanisme par lequel les protéines p63 et ZNF148, en agissant sur la transcription d'une région amplificatrice du gène CCND1, favorisent la surexpression de la cycline D1 pour renforcer la prolifération des cellules tumorales
Head and neck tumors are common and can become aggressive in advanced stages, making treatment challenging. Understanding the molecular mechanisms underlying tumor development is crucial. Oncogenic transcription factors like p63 drive cancer progression, but whether they require additional cofactors remains unclear. Using proteomics, we identified ZNF148, a zinc-finger protein that cooperates with p63. In tumor cells, p63 and ZNF148 bind to each other and colocalize on DNA to regulate shared target genes. Notably, they transcribe an enhancer RNA that controls the expression of cyclin D1, a protein critical for tumor growth. Our findings reveal a p63/ZNF148/cyclin D1 axis driving cancer progression, offering insights into the molecular basis of head and neck tumors. 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.
Proceedings of the National Academy of Sciences , article en libre accès, 2025