Anaplastic thyroid carcinoma (ATC) is an extremely aggressive thyroid cancer sub-type, refractory to current medical treatment. Among various epigenetic anticancer drugs, BET inhibitors (BETi) are considered an appealing novel class of compounds. BETi target the Bromodomain and Extra-Terminal (BET) proteins that act as regulators of gene transcription, interacting with histone acetyl groups. The goal of this study is to delineate which pathway underlie the biological effects derived from BET inhibition, in order to find new potential therapeutic targets in ATC. We investigated effects of BET inhibition on two human anaplastic thyroid cancer-derived cell lines (FRO and SW1736). The treatment with two BETi, JQ1 and I-BET762, decreased cell viability, reduced cell cycle S-phase and determined cell death. In order to find BETi effectors, FRO and SW1736 were subjected to a global transcriptome analysis after JQ1 treatment. A significant portion of deregulated genes belongs to cell cycle regulators. Among them, MCM5 was decreased at both mRNA and protein levels in both tested cell lines. ChIP experiments indicate that MCM5 is directly bound by the BET protein BRD4. MCM5 silencing reduced cell proliferation, thus underlining its involvement in the block of proliferation induced by BETi. Furthermore, MCM5 immunohistochemical evaluation in human thyroid tumor tissues demonstrated its over-expression in several papillary thyroid carcinomas and in all ATCs. MCM5 was also over-expressed in a murine model of ATC, and JQ1 treatment reduced Mcm5 mRNA expression in two murine ATC cell lines. Thus, MCM5 could represent a new target in the therapeutic approach against ATC.
The TSH receptor (TSHR) and sodium/iodide symporter (NIS) are key players in radioiodinebased treatment of differentiated thyroid cancers. While NIS (SLC5AS) expression is diminished/lost in most thyroid tumors, TSHR is usually preserved. To examine the mechanisms that regulate the expression of NIS and TSHR genes in thyroid tumor cells, we analyzed their expression after inhibition of ras-BRAF-MAPK and PI3K-Akt-mTOR pathways and the epigenetic control occurring at the gene promoter level in four human thyroid cancer cell lines. Quantitative real-time PCR was used to measure NIS and TSHR mRNA in thyroid cancer cell lines (TPC-1, BCPAP, WRO, and FTC-133). Western blotting was used to assess the levels of total and phosphorylated ERK and Akt. Chromatin immunoprecipitation was performed for investigating histone post-translational modifications of the TSHR and NIS genes. ERK and Akt inhibitors elicited different responses of the cells in terms of TSHR and NIS mRNA levels. Akt inhibition increased NIS transcript levels and reduced those of TSHR in FTC-133 cells but had no significant effects in BCPAP. ERK inhibition increased the expression of both genes in BCPAP cells but had no effects in FTC-133. Histone posttranslational modifications observed in the basal state of the four cell lines as well as in BCPAP treated with ERK inhibitor and FTC-133 treated with Akt inhibitor show cell-and gene-specific differences. In conclusion, our data indicate that in thyroid cancer cells the expression of TSHR and NIS genes is differently controlled by multiple mechanisms, including epigenetic events elicited by major signaling pathways involved in thyroid tumorigenesis.
Hu antigen R (HuR) is indeed one of the most studied RNA-binding protein (RBP) since its fundamental role both in tumorigenesis and cancer progression. For this reason, downregulation in HuR protein levels or inhibition of HuR biological function are, nowadays, attractive goals in cancer research. Here, we examined the antitumor effects of CMLD-2 in four thyroid cancer cell lines (SW1736, 8505 C, BCPAP and K1). Indeed, CMLD-2 competitively binds HuR protein disrupting its interaction with RNA-targets. 35 μM CLMD-2 produced a significant downregulation in thyroid cancer cell viability, coupled to an increase in apoptosis. Moreover, CMLD-2 treatment hindered both migration and colony formation ability. MAD2 is a microtubules-associated protein known to be greatly overexpressed in cancer and correlating with tumor aggressiveness. Furthermore, MAD2 is known to be a HuR target. CMLD-2 treatment induced a strong MAD2 downregulation and rescue experiments depicted it as a key effector in HuR-mediated in cancer. Altogether, these data contributed to foster HuR inhibition as valid antineoplastic treatment in thyroid cancer, highlighting MAD2 as a novel therapeutic target.
Mutations in the hTERT promoter responsible for constitutive telomerase activity are the most frequent genetic alteration detected in anaplastic thyroid cancer (ATC), and proposed as diagnostic and prognostic biomarker in these tumours. In this study we analyzed hTERT expression in a series of human ATCs and investigated the effects of small-interfering RNA-mediated silencing of hTERT on viability and migration and invasive properties of three human ATC cell lines. Expression of hTERT mRNA resulted increased in 8/10 ATCs compared to normal thyroid tissues. Silencing of hTERT in CAL-62, 8505C and SW1736 cells did not modify telomere length but determined a significant decrease (about 50%) of cell proliferation in all cell lines and a great reduction (about 50%) of migration and invasion capacity. These finding demonstrate that hTERT may be considered as a molecular target for ATC treatment.
High cytotoxic and antimetastatic activities against anaplastic thyroid cancer are displayed by cationic complexes [RuX(CO)(dppb)(phen)]Y (X = Y = OAc, OPiv, SAc, and NCS; X = Cl and Y = PF6).
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