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Publications

Journal Article Ppublish

PubMed: 40623191 DOI: 10.1073/pnas.2500579122

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

Proc Natl Acad Sci U S A 122(28):e2500579122

Authors: Rosalba Pecorari, Mara Mancini, Artem Smirnov, Giacomo Corleone, Flavia Novelli, Anna Maria Lena, Mariacristina Franzese Canonico, Manuela Montanaro, Angela Cappello, Andrea Sacconi, Gabriella Misso, Michela Falco, Chiara Tammaro, Fabiola Ciccosanti, Mauro Piacentini, Manuel Scimeca, Michele Caraglia, Giovanni Blandino, Alessandro Mauriello, Maurizio Fanciulli, Gerry Melino, Eleonora Candi

Affiliations

  • 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.
  • Struttura di Area Funzionale di Ricerca Unit (SAFU), Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, Istituto di Ricovero e Cura a Carattere Scientifico Regina Elena National Cancer Institute, Rome 00144, Italy.
  • Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96816.
  • Biostatistics, Bioinformatics and Clinical Trial Center, Istituto di Ricovero e Cura a Carattere Scientifico Regina Elena National Cancer Institute, Rome 00144, Italy.
  • Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples 80138, Italy.
  • Laboratory of Precision and Molecular Oncology, Biogem Scarl, Institute of Genetic Research, Ariano Irpino 83031, Italy.
  • Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases Istituto di Ricovero e Cura a Carattere Scientifico "L. Spallanzani", Rome 00149, Italy.
  • Translational Oncology Research Unit, Department of Research, Diagnosis and Innovative Technologies, Istituto di Ricovero e Cura a Carattere Scientifico Regina Elena National Cancer Institute, Rome 00144, Italy.

Abstract

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.

MeSH

Cells, Genes, Carcinoma, Squamous Cell, Neoplasms, Squamous Cell Carcinoma Of Head And Neck, Therapeutics