The Sonic hedgehog (Shh) pathway plays a critical role in hair follicle physiology and is constitutively active in basal cell carcino- mas (BCCs), the most common human malignancy. Type 3 iodo- thyronine deiodinase (D3), the thyroid hormone-inactivating en- zyme, 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.
ESonic 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, and Domenico Salvatore. Endocrinology. September 4, 2007. doi: 10.1073 pnas.0706754104