Loss of p53 activates thyroid hormone via type 2 deiodinase and enhances DNA damage

Annarita Nappi, Caterina Miro, Antonio Pezone, Alfonso Tramontano, Emery Cicco, Serena Sagliocchi, Annunziata Gaetana Cicatiello, Melania Murolo, Sepehr Torabinejad, Elena Abbotto, Giuseppina Caiazzo, Maddalena Raia, Mariano Stornaiuolo, Dario Antonini, Gabriella Fabbrocini, Domenico Salvatore, Vittorio Enrico Avvedimento and Monica Dentice ()
Additional contact information
Annarita Nappi: University of Naples “Federico II”
Caterina Miro: University of Naples “Federico II”
Antonio Pezone: University of Naples “Federico II”
Alfonso Tramontano: University of Campania “L. Vanvitelli”
Emery Cicco: University of Naples “Federico II”
Serena Sagliocchi: University of Naples “Federico II”
Annunziata Gaetana Cicatiello: University of Naples “Federico II”
Melania Murolo: University of Naples “Federico II”
Sepehr Torabinejad: University of Naples “Federico II”
Elena Abbotto: University of Genoa
Giuseppina Caiazzo: University of Naples “Federico II”
Maddalena Raia: CEINGE, Biotecnologie Avanzate S.c.a.r.l.
Mariano Stornaiuolo: University of Naples “Federico II”
Dario Antonini: University of Naples “Federico II”
Gabriella Fabbrocini: University of Naples “Federico II”
Domenico Salvatore: CEINGE, Biotecnologie Avanzate S.c.a.r.l.
Vittorio Enrico Avvedimento: University of Naples “Federico II”
Monica Dentice: University of Naples “Federico II”

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract The Thyroid Hormone (TH) activating enzyme, type 2 Deiodinase (D2), is functionally required to elevate the TH concentration during cancer progression to advanced stages. However, the mechanisms regulating D2 expression in cancer still remain poorly understood. Here, we show that the cell stress sensor and tumor suppressor p53 silences D2 expression, thereby lowering the intracellular THs availability. Conversely, even partial loss of p53 elevates D2/TH resulting in stimulation and increased fitness of tumor cells by boosting a significant transcriptional program leading to modulation of genes involved in DNA damage and repair and redox signaling. In vivo genetic deletion of D2 significantly reduces cancer progression and suggests that targeting THs may represent a general tool reducing invasiveness in p53-mutated neoplasms.

Date: 2023
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DOI: 10.1038/s41467-023-36755-y

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