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Cooperation of histone deacetylase inhibitors SAHA and valproic acid in promoting sodium/iodide symporter expression and function in rat Leydig testicular carcinoma cells

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Abstract

The presence of the sodium/iodide symporter (NIS) is the prerequisite for the use of the radioiodine in the treatment of thyroid cancer. Thus, stimulators of NIS expression and function are currently investigated in cellular models of various human malignancies, also including extrathyroid cancers. In this study, we analyzed the effects of the histone deacetylase inhibitors (HDACi), suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA), on NIS expression and function in rat Leydig testicular carcinoma cells (LC540). LC540 cells were exposed to SAHA 3 μM and VPA 3 mM (alone and in combination), and cell viability evaluated by MTT assay and cell counting, NIS mRNA and protein levels by using, respectively, real-time RT-PCR and western blotting. NIS function was evaluated by iodide uptake assay. We found that both HDACi were able to stimulate the transcription of NIS gene, but not its protein expression, while the association of SAHA and VPA increased both NIS transcript and protein levels, resulting in significant sixfold enhancement of radioiodine uptake capacity of LC540 cells. These data demonstrate the presence of an epigenetic control of NIS expression in Leydig tumor cells, suggesting the possibility to use the combination of these two HDACi for a radioiodine-based treatment of these malignancies.

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Acknowledgments

This study was supported by the Fondazione Umberto Di Mario and from funds of the Italian Ministry of Instruction, University and Research (MIUR, PRIN 2008) to D. R. and by Associazione Italiana Ricerca Cancro (AIRC; Project No. Grant No. IG 10296). V. M. is fellow in the PhD course of Pharmaceutical Sciences at the University of Catanzaro.

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Authors and Affiliations

  1. Department of Health Sciences, University of Catanzaro ‘Magna Graecia’, Viale Europa, loc. Germaneto, 88100, Catanzaro, Italy

    V. Maggisano, M. Celano, M. D’Agostino & D. Russo

  2. Department of Medical and Biological Sciences, Azienda Ospedaliero-Universitaria “S. Maria della Misericordia”, University of Udine, 33100, Udine, Italy

    C. Puppin & G. Damante

  3. Department of Internal Medicine and Medical Specialties, University of Rome “Sapienza”, 00161, Rome, Italy

    M. Sponziello & S. Filetti

  4. Department of Urology, University of Modena and Reggio Emilia, 41100, Modena, Italy

    S. Micali

  5. Department of Drug Sciences and Health Products, University of Messina and IRCCS Centro Neurolesi ‘Bonino-Pulejo’, 98100, Messina, Italy

    M. Navarra

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  1. V. Maggisano
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  2. C. Puppin
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  3. M. Celano
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  4. M. D’Agostino
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  7. M. Navarra
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  9. S. Filetti
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  10. D. Russo
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Correspondence to D. Russo.

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Maggisano, V., Puppin, C., Celano, M. et al. Cooperation of histone deacetylase inhibitors SAHA and valproic acid in promoting sodium/iodide symporter expression and function in rat Leydig testicular carcinoma cells. Endocrine 45, 148–152 (2014). https://doi.org/10.1007/s12020-013-9972-4

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  • DOI: https://doi.org/10.1007/s12020-013-9972-4

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