title: CD44 proteolysis increases CREB phosphorylation and sustains proliferation of thyroid cancer cells.
abstract: CD44 is a marker of cancer stem-like cells and epithelial-mesenchymal transition that is overexpressed in many cancer types, including thyroid carcinoma. At extracellular and intramembranous domains, CD44 undergoes sequential metalloprotease- and γ-secretase-mediated proteolytic cleavage, releasing the intracellular protein fragment CD44-ICD, which translocates to the nucleus and activates gene transcription. Here, we show that CD44-ICD binds to the transcription factor CREB, increasing S133 phosphorylation and CREB-mediated gene transcription. CD44-ICD enhanced CREB recruitment to the cyclin D1 promoter, promoting cyclin D1 transcription and cell proliferation. Thyroid carcinoma cells harboring activated RET/PTC, RAS, or BRAF oncogenes exhibited CD44 cleavage and CD44-ICD accumulation. Chemical blockade of RET/PTC, BRAF, metalloprotease, or γ-secretase were each sufficient to blunt CD44 processing. Furthermore, thyroid cancer cell proliferation was obstructed by RNA interference-mediated knockdown of CD44 or inhibition of γ-secretase and adoptive CD44-ICD overexpression rescued cell proliferation. Together, these findings reveal a CD44-CREB signaling pathway that is needed to sustain cancer cell proliferation, potentially offering new molecular targets for therapeutic intervention in thyroid carcinoma.
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, L. Califano, Università di Napoli Federico II c/o Istituto di Endocrinologia e Oncologia Sperimentale del CNR, Napoli, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: De Falco
authors.forename: Anna
authors.initials: A
authors.lastname: Tamburrino
authors.forename: Simona
authors.initials: S
authors.lastname: Ventre
authors.forename: Maria Domenica
authors.initials: MD
authors.lastname: Castellone
authors.forename: Mouhannad
authors.initials: M
authors.lastname: Malek
authors.forename: Serge N
authors.initials: SN
authors.lastname: Manié
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics; D000818:Animals; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000235:genetics; D009857:Oncogenes / Q000187:drug effects; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D059748:Proteolysis; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014158:Transcription, Genetic
chemical_list: C530104:CCND1 protein, human; C497483:CD44 protein, human; C530106:Ccnd1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D018960:Hyaluronan Receptors; D019938:Cyclin D1; D051096:Proto-Oncogene Proteins c-ret; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D053829:Amyloid Precursor Protein Secretases; D045726:Metalloproteases