Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes

Monica Dentice, Cristina Luongo, Stephen Huang, Raffaele Ambrosio, Antonia Elefante, Delphine Mirebeau-Prunier, Ann Marie Zavacki, Gianfranco Fenzi, Marina Grachtchouk, Mark Hutchin, Andrzej A. Dlugosz, Antonio C. Bianco, Caterina Missero, P. Reed Larsen, Domenico Salvatore

Research output: Contribution to journalArticle

118 Scopus citations

Abstract

The Sonic hedgehog (Shh) pathway plays a critical role in hair follicle physiology and is constitutively active in basal cell carcinomas (BCCs), the most common human malignancy. Type 3 iodothyronine deiodinase (D3), the thyroid hormone-inactivating enzyme, is frequently expressed in proliferating and neoplastic cells, but its role in this context is unknown. Here we show that Shh, through Gli2, directly induces D3 in proliferating keratinocytes and in mouse and human BCCs. We demonstrate that Gli-induced D3 reduces intracellular active thyroid hormone, thus resulting in increased cyclin D1 and keratinocyte proliferation. D3 knockdown caused a 5-fold reduction in the growth of BCC xenografts in nude mice. Shh-induced thyroid hormone degradation via D3 synergizes with the Shh-mediated reduction of the type 2 deiodinase, the thyroxine-activating enzyme, and both effects are reversed by cAMP. This previously unrecognized functional cross-talk between Shh/Gli2 and thyroid hormone in keratinocytes is a pathway by which Shh produces its proliferative effects and offers a potential therapeutic approach to BCC.

Original languageEnglish (US)
Pages (from-to)14466-14471
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number36
DOIs
StatePublished - Sep 4 2007

Keywords

  • Basal cell carcinoma
  • Cancer
  • Differentiation
  • Thyroxine

ASJC Scopus subject areas

  • Genetics
  • General

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    Dentice, M., Luongo, C., Huang, S., Ambrosio, R., Elefante, A., Mirebeau-Prunier, D., Zavacki, A. M., Fenzi, G., Grachtchouk, M., Hutchin, M., Dlugosz, A. A., Bianco, A. C., Missero, C., Larsen, P. R., & Salvatore, D. (2007). Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes. Proceedings of the National Academy of Sciences of the United States of America, 104(36), 14466-14471. https://doi.org/10.1073/pnas.0706754104