The sonic hedgehog-induced type 3 deiodinase facilitates tumorigenesis of basal cell carcinoma by reducing Gli2 inactivation.
Thyroid hormone (TH) is an important regulator of growth, development, and metabolism. Most of the active TH T3 is generated by peripheral TH metabolism mediated by the iodothyronine deiodinases. Type 3 deiodinase (D3) inactivates T3 via specific deiodination reactions. It is an oncofetal protein frequently expressed in neoplastic tissues and is a direct target of the sonic hedgehog (Shh) pathway in basal cell carcinomas (BCCs). However, the molecular mechanisms triggered by T3 in BCC are still mostly unrevealed. Here, we demonstrate that D3 action is critical in the proliferation and survival of BCC cells. D3 depletion or T3 treatment induce apoptosis of BCC cells and attenuate Shh signaling. This is achieved through a direct impairment of Gli2 protein stability by T3. T3 induces protein kinase A, which in turn destabilizes Gli2 protein via its C-terminal degron. Finally, in a mouse model of BCC, T3-topical treatment significantly reduces tumor growth. These results demonstrate the existence of a previously unrecognized cross talk between TH and Gli2 oncogene, providing functional and mechanistic evidence of the involvement of TH metabolism in Shh-induced cancer. TH-mediated Gli2 inactivation would be beneficial for therapeutically purposes, because the inhibition of Shh-Gli2 signaling is an attractive target for several anticancer drugs, currently in clinical trials.
Department of Clinical Medicine Surgery (C.L., M.D.), University of Naples Federico II, 80131 Naples, Italy; Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Studio di Diagnostica Nucleare (R.A.), 80142 Naples, Italy; Institute of Experimental Endocrinology and Oncology G. Salvatore-Consiglio Nazionale delle Ricerche (S.S.), 80131 Naples, Italy; Department of Dermatology and Comprehensive Cancer Center (A.A.D.), University of Michigan, Ann Arbor, Michigan 48109; and Centro di Ingegneria Genetica Biotecnologie Avanzate Scarl (C.M.), 80131 Naples, Italy.
Cristina
C
Luongo
Raffaele
R
Ambrosio
Salvatore
S
Salzano
Andrzej A
AA
Dlugosz
Caterina
C
Missero
Monica
M
Dentice
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D002280:Basal Cell Carcinoma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D013963:Thyroid Hormones / Q000378:metabolism / Q000494:pharmacology*; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology*; D000075746:Zinc Finger Protein Gli2
C000618551:Gli2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D013963:Thyroid Hormones; D000075746:Zinc Finger Protein Gli2; D014284:Triiodothyronine; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase