MCM5 as a target of BET inhibitors in thyroid cancer cells

Abstract

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.