Pecorari Rosalba, Mancini Mara, Smirnov Artem, Corleone Giacomo, Novelli Flavia, Lena Anna Maria, Franzese Canonico Mariacristina, 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
Istituto di Ricovero e Cura a Carattere Scientifico Istituto Dermopatico dell'Immacolata (IDI-IRCCS), Biochemistry Laboratory, Rome 00144, Italy.
Department of Experimental Medicine, University of Rome "Tor Vergata", Rome 00133, Italy.
Proc Natl Acad Sci U S A. 2025 Jul 15;122(28):e2500579122. doi: 10.1073/pnas.2500579122. Epub 2025 Jul 7.
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.
头颈部鳞状细胞癌（HNSCC）是一种常见且侵袭性强的恶性肿瘤。虽然在低级别癌症的治疗方面取得了显著进展，但晚期HNSCC的治疗仍然具有挑战性。在此，我们采用蛋白质组学方法来寻找癌基因p63的结合伴侣，p63是HNSCC中最常扩增的转录因子。我们鉴定出一种锌指蛋白ZNF148，它在癌细胞中与p63共表达且与p63直接结合。基因组占据分析确定了CCND1基因上游一个功能性转录增强子衍生RNA（eRNA），这两个因子都占据该区域。从机制上讲，p63和ZNF148控制该eRNA的转录，导致细胞周期蛋白D1过表达，从而增强肿瘤细胞增殖。重要的是，这一轴对癌细胞具有特异性，在正常上皮细胞中保持无活性。这些因子和eRNA的表达水平在癌症中呈正相关，并与晚期和转移相关。总体而言，我们的数据揭示了一条控制HNSCC进展的分子途径，并确定了癌症治疗的潜在选择性靶点。
