EVALUATION OF HISTONE DEACETYLASE INHIBITOR EFFECTS ON THYROID CANCER

Abstract Histone deacetylases (HDACs) play a crucial role in the proper regulation of cellular functions through their connection with chromatin and transcriptional regulation. Alterations in HDAC activity have been reported in several types of cancer encouraging development of HDAC inhibitors (HDACis) for cancer treatment. The antitumor activity of HDACi has been demonstrated, in clinical trials, in both solid and non solid neoplasias at doses well tolerated by patients. However, the molecular basis for their tumor selectivity is unknown. Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, having a poor prognosis and being refractory to conventional chemo- and radiotherapy. To the aim to find an innovative therapy for the treatment of ATCs, we studied the effects of two potent HDACis, SAHA and MS-275, on rat thyroid cell lines transformed by the v-ras-Ki oncogene which is frequently mutated in ATCs. We show that: i) HDAC 1 and HDAC 2 are overexpressed in anaplastic thyroid carcinomas compared to normal thyroid; ii) SAHA and MS-275 induce apoptosis selectively in completely transformed rat thyroid cells; iii) TNF-related apoptosis-inducing ligand (TRAIL) is the main mediator of cell death induced by SAHA; iv) SAHA stabilize TRAIL protein by affecting its proteasome-mediated degradation.