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MCM5 as a target of BET inhibitors in thyroid cancer cells
Catia Mio1, Elisa Lavarone1, Ketty Conzatti1
1Department of Medical and Biological SciencesUniversity of Udine, Udine, Italy.
Abstract:
Anaplastic thyroid carcinoma (ATC) is an extremely aggressive thyroid cancer subtype, refractory to the current medical treatment. Among various epigenetic anticancer drugs, bromodomain and extra-terminal inhibitors (BETis) are considered to be an appealing novel class of compounds. BETi target the bromodomain and extra-terminal of BET proteins that act as regulators of gene transcription, interacting with histone acetyl groups. The goal of this study is to delineate which pathway underlies the biological effects derived from BET inhibition, in order to find new potential therapeutic targets in ATC. We investigated the effects of BET inhibition on two human anaplastic thyroid cancer-derived cell lines (FRO and SW1736). The treatment with two BETis, 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. Chromatin immunoprecipitation (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 BETis. Furthermore, MCM5 immunohistochemical evaluation in human thyroid tumor tissues demonstrated its overexpression in several papillary thyroid carcinomas and in all ATCs. MCM5 was also overexpressed 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.
Insights
Bromodomain and extra-terminal inhibitors (BETis) show promise against anaplastic thyroid carcinoma (ATC). These inhibitors decrease cell viability and target MCM5, a protein overexpressed in ATC, suggesting MCM5 as a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Anaplastic thyroid carcinoma (ATC) is an aggressive cancer resistant to current treatments.
- Bromodomain and extra-terminal inhibitors (BETis) are emerging epigenetic drugs targeting gene transcription regulators.
Purpose of the Study:
- To identify pathways affected by BET inhibition in ATC.
- To discover novel therapeutic targets for ATC.
Main Methods:
- Treatment of human ATC cell lines (FRO, SW1736) with BETis (JQ1, I-BET762).
- Global transcriptome analysis to identify BETi-affected genes.
- Chromatin immunoprecipitation (ChIP) to assess protein-DNA interactions.
- Immunohistochemical evaluation of MCM5 in human and murine thyroid tumors.
Main Results:
- BET inhibition decreased cell viability, induced cell death, and arrested the cell cycle in ATC cell lines.
- Transcriptome analysis revealed deregulation of cell cycle genes, notably MCM5.
- MCM5 was found to be directly bound by BRD4 and its silencing inhibited proliferation.
- MCM5 was overexpressed in human ATCs and papillary thyroid carcinomas, and in a murine ATC model.
Conclusions:
- MCM5 is a direct target of BET proteins and plays a role in BETi-induced proliferation block.
- MCM5 overexpression in ATC suggests it as a potential therapeutic target for this aggressive cancer.
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