The NANOG Transcription Factor Induces Type 2 Deiodinase Expression and Regulates the Intracellular Activation of Thyroid Hormone in Keratinocyte Carcinomas

Abstract

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.

Thyroid hormone action in epidermal development and homeostasis and its implications in the pathophysiology of the skin

“…These findings confirmed the concept that D3 is essential for the early stages of tumorigenesis [ 38 , 63 ] and demonstrated that an enhanced TH signal is associated with high metastatic risk. Finally, the functional link between TH activation by D2 and keratinocyte carcinomas was recently confirmed by the finding that D2 is regulated by the transcription factor NANOG in basal cell carcinomas and squamous cell carcinomas and that D2 and NANOG expression are closely associated during the progression of keratinocyte carcinomas [ 68 ].…”

A tEMTing target? Clinical and experimental evidence for epithelial-mesenchymal transition in the progression of cutaneous squamous cell carcinoma (a scoping systematic review)

“…The subsequently induced EMT could be reversed with the inverse agonist XCT790. Nappi et al [ 143 ] reported on a link between thyroid hormones, EMT, and tumor stage. NANOG and Deiodinase 2 (D2) were proportionately increased significantly with increased cSCC stage.…”

Topical L‐thyroxine: The Cinderella among hormones waiting to dance on the floor of dermatological therapy?

“…Very recent epidemiological data support the long‐suspected carcinogenic effect of long‐term systemic T4 therapy: the latter was found to be associated with a significantly increased rate of several different types of cancer in Swedish patients, especially among women 213 . Together with the body of work published by Dentice and collaborators that has highlighted the involvement of TH and their deiodinases in carcinoma‐associated EMT, squamous cell carcinoma (SCC) and basal cell carcinoma, 55,170,214,215 this strongly argues against long‐term topical T4 therapy. Instead, it would appear well‐advised to limit any form of topical T4 therapy in dermatology to maximally a couple of weeks, or perhaps ideally, to a pulse therapy regimen with sufficiently long treatment‐free intervals so as to evade or minimize the risk of carcinogenicity.…”