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

被引:17
作者
Nappi, Annarita [1 ]
Miro, Caterina [1 ]
Pezone, Antonio [2 ]
Tramontano, Alfonso [3 ]
Di Cicco, Emery [1 ]
Sagliocchi, Serena [1 ]
Cicatiello, Annunziata Gaetana [1 ]
Murolo, Melania [1 ]
Torabinejad, Sepehr [1 ]
Abbotto, Elena [4 ]
Caiazzo, Giuseppina [1 ]
Raia, Maddalena [5 ]
Stornaiuolo, Mariano [6 ]
Antonini, Dario [2 ]
Fabbrocini, Gabriella [1 ]
Salvatore, Domenico [5 ,7 ]
Avvedimento, Vittorio Enrico [8 ]
Dentice, Monica [1 ,5 ]
机构
[1] Univ Naples Federico II, Dept Clin Med & Surg, I-80131 Naples, Italy
[2] Univ Naples Federico II, Dept Biol, I-80126 Naples, Italy
[3] Univ Campania L Vanvitelli, Dept Precis Med, I-80138 Naples, Italy
[4] Univ Genoa, Dept Expt Med, I-16132 Genoa, Italy
[5] CEINGE, Biotecnol Avanzate Scarl, I-80131 Naples, Italy
[6] Univ Naples Federico II, Dept Pharm, I-80149 Naples, Italy
[7] Univ Naples Federico II, Dept Publ Hlth, I-80131 Naples, Italy
[8] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, I-80131 Naples, Italy
基金
欧盟地平线“2020”;
关键词
CELL-MIGRATION; CANCER-RISK; GENE; EXPRESSION; MUTATIONS; MECHANISM; OXIDATION; PATHWAY; PROTEIN; CODE;
D O I
10.1038/s41467-023-36755-y
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Thyroid hormones have an important role in fostering tumour progression, however their upstream regulators are less clear. Here, the authors identify the thyroid hormone activating enzyme type 2 deiodinase as a p53 target gene and demonstrate its contribution to tumour progression in p53 mutant squamous cell carcinoma. 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.
引用
收藏
页数:18
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