p63 orchestrates serine and one carbon metabolism enzymes expression in head and neck cancer

Biology Direct · 10 authors, 8 centres

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TL;DR

This preclinical study shows that the transcription factor p63 directly binds and regulates the expression of enzymes in serine biosynthesis and one-carbon metabolism in head and neck squamous cell carcinoma (HNSCC) cells, and that higher expression of TP63 and its target enzymes is associated with worse patient survival.

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The study investigates the role of the transcription factor p63 in regulating metabolic pathways in head and neck squamous cell carcinoma (HNSCC). Using the FaDu HNSCC cell line, the authors demonstrate through chromatin immunoprecipitation sequencing (ChIP-seq) data visualization that p63 binds the promoter regions of genes involved in serine biosynthesis and one-carbon metabolism, including PHGDH, PSAT1, PSPH, and MTHFD2. Silencing p63 in these cells reduces the mRNA and protein levels of these enzymes, particularly PSPH. Analysis of public transcriptomic datasets (GSE12452, GSE181919) indicates that higher expression of TP63 and its target enzymes correlates with poorer overall survival in HNSCC patients. The work is preclinical, based on cell line models and bioinformatics analysis of human tissue datasets, and does not involve direct human intervention.

STUDY TYPE

other

SPECIALTY

oncology

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AI pipeline

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ORIGINAL PAPER

PMC10636826

p63 orchestrates serine and one carbon metabolism enzymes expression in head and neck cancer

Biology Direct

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ABSTRACT

Abstract Background Head and neck squamous cell carcinoma (HNSCC) is characterized by high proliferation and limited differentiation. The altered expression of the p53 family members, and specifically of p63, represents a pivotal event in the pathogenesis of HNSCC. Physiologically, p63 affects metabolism through the direct transactivation of the enzyme hexokinase 2, and subsequently controls the proliferation of epithelial cells; nonetheless, its role in cancer metabolism is still largely unclear. The high energetic demand of cancer and the consequent needs of a metabolic reshape, also involve the serine and glycine catabolic and anabolic pathways, including the one carbon metabolism (OCM), to produce energetic compounds (purines) and to maintain cellular homeostasis (glutathione and S-adenosylmethionine). Results The involvement in serine/glycine starvation by other p53 family members has been reported, including HNSCC. Here, we show that in HNSCC p63 controls the expression of the enzymes regulating the serine biosynthesis and one carbon metabolism. p63 binds the promoter region of genes involved in the serine biosynthesis as well as in the one carbon metabolism. p63 silencing in a HNSCC cell line affects the mRNA and protein levels of these selected enzymes. Moreover, the higher expression of TP63 and its target enzymes, negatively impacts on the overall survival of HNSCC patients. Conclusion These data indicate a direct role of p63 in the metabolic regulation of HNSCC with significant clinical effects. Supplementary Information The online version contains supplementary material available at 10.1186/s13062-023-00426-1. Keywords: Head and neck cancer, p53 family, p63, Serine, One carbon metabolism

CITATION EXPORT

Angela Cappello, Giulia Tosetti, Artem Smirnov et al.. p63 orchestrates serine and one carbon metabolism enzymes expression in head and neck cancer. Biology Direct. (2023). https://doi.org/10.1186/s13062-023-00426-1

AUTHORS

10 · 8 CENTRES

Angela Cappello, Giulia Tosetti, Artem Smirnov, Carlo Ganini, Xue Yang, Yufang Shi, Ying Wang, Gerry Melino, Francesca Bernassola, Eleonora Candi

1Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
2Interdisciplinary Department of Medicine, University of Bari “Aldo Moro”, 70121 Bari, Italy
3Istituto Dermopatico dell’Immacolata, IDI-IRCCS, 00167 Rome, Italy
4Division of Medical Oncology, A.O.U. Policlinico di Bari, 70124 Bari, Italy
5Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438 China
6National Center for Liver Cancer, Shanghai, 201805 China
7The Third Affiliated Hospital of Soochow University and State Key Laboratory of Radiation Medicine and Protection, Institute for Translational Medicine, Soochow University, Suzhou, China
8CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China