TY - JOUR
T1 - The NANOG transcription factor induces type 2 deiodinase expression and regulates the intracellular activation of thyroid hormone in keratinocyte carcinomas
AU - Nappi, Annarita
AU - Di Cicco, Emery
AU - Miro, Caterina
AU - Cicatiello, Annunziata Gaetana
AU - Sagliocchi, Serena
AU - Mancino, Giuseppina
AU - Ambrosio, Raffaele
AU - Luongo, Cristina
AU - Di Girolamo, Daniela
AU - De Stefano, Maria Angela
AU - Porcelli, Tommaso
AU - Stornaiuolo, Mariano
AU - Dentice, Monica
N1 - Funding Information:
Funding: This work was supported by grants from AIRC to M.D. (IG 13065), by the ERCStG2014 grant from European Research Council under the European Union’s Horizon2020 Programme (STARS – 639548) and by the EU FP7 contract Thyrage (grant number 666869) to M.D.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/3
Y1 - 2020/3
N2 - Type 2 deiodinase (D2), the principal activator of thyroid hormone (TH) signaling in target tissues, is expressed in cutaneous squamous cell carcinomas (SCCs) during late tumorigenesis, and its repression attenuates the invasiveness and metastatic spread of SCC. Although D2 plays multiple roles in cancer progression, nothing is known about the mechanisms regulating D2 in cancer. To address this issue, we investigated putative upstream regulators of D2 in keratinocyte carcinomas. We found that the expression of D2 in SCC cells is positively regulated by the NANOG transcription factor, whose expression, besides being causally linked to embryonic stemness, is associated with many human cancers. We also found that NANOG binds to the D2 promoter and enhances D2 transcription. Notably, blockage of D2 activity reduced NANOG-induced cell migration as well as the expression of key genes involved in epithelial–mesenchymal transition in SCC cells. In conclusion, our study reveals a link among endogenous endocrine regulators of cancer, thyroid hormone and its activating enzyme, and the NANOG regulator of cancer biology. These findings could provide the basis for the development of TH inhibitors as context-dependent anti-tumor agents.
AB - Type 2 deiodinase (D2), the principal activator of thyroid hormone (TH) signaling in target tissues, is expressed in cutaneous squamous cell carcinomas (SCCs) during late tumorigenesis, and its repression attenuates the invasiveness and metastatic spread of SCC. Although D2 plays multiple roles in cancer progression, nothing is known about the mechanisms regulating D2 in cancer. To address this issue, we investigated putative upstream regulators of D2 in keratinocyte carcinomas. We found that the expression of D2 in SCC cells is positively regulated by the NANOG transcription factor, whose expression, besides being causally linked to embryonic stemness, is associated with many human cancers. We also found that NANOG binds to the D2 promoter and enhances D2 transcription. Notably, blockage of D2 activity reduced NANOG-induced cell migration as well as the expression of key genes involved in epithelial–mesenchymal transition in SCC cells. In conclusion, our study reveals a link among endogenous endocrine regulators of cancer, thyroid hormone and its activating enzyme, and the NANOG regulator of cancer biology. These findings could provide the basis for the development of TH inhibitors as context-dependent anti-tumor agents.
KW - Deiodinases
KW - Skin cancer
KW - Thyroid hormone
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U2 - 10.3390/cancers12030715
DO - 10.3390/cancers12030715
M3 - Article
AN - SCOPUS:85082104535
VL - 12
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 3
M1 - 715
ER -