Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes.
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.
Dentice
Monica
M
Department of Molecular and Clinical Endocrinology and Oncology, University of Naples Federico II, 80131 Naples, Italy, and Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, MA 02115, USA.
Luongo
Cristina
C
Huang
Stephen
S
Ambrosio
Raffaele
R
Elefante
Antonia
A
Mirebeau-Prunier
Delphine
D
Zavacki
Ann Marie
AM
Fenzi
Gianfranco
G
Grachtchouk
Marina
M
Hutchin
Mark
M
Dlugosz
Andrzej A
AA
Bianco
Antonio C
AC
Missero
Caterina
C
Larsen
P Reed
PR
Salvatore
Domenico
D
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006727:Hormone Antagonists / Q000378:metabolism*; D007453:Iodide Peroxidase / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology*; D013963:Thyroid Hormones / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1
D053823:Hedgehog Proteins; D006727:Hormone Antagonists; D015513:Oncogene Proteins; C465570:Shh protein, mouse; D013963:Thyroid Hormones; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase