title: MCM5 as a target of BET inhibitors in thyroid cancer cells.
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.
authors.affiliation: Department of Medical and Biological SciencesUniversity of Udine, Udine, Italy.
authors.forename: Catia
authors.initials: C
authors.lastname: Mio
authors.affiliation: Department of Medical and Biological SciencesUniversity of Udine, Udine, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Lavarone
authors.affiliation: Department of Medical and Biological SciencesUniversity of Udine, Udine, Italy.
authors.forename: Ketty
authors.initials: K
authors.lastname: Conzatti
authors.affiliation: Department of Medical and Biological SciencesUniversity of Udine, Udine, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Baldan
authors.affiliation: Department of Medical and Biological SciencesUniversity of Udine, Udine, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Toffoletto
authors.affiliation: Department of Medical and Biological SciencesUniversity of Udine, Udine, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Puppin
authors.affiliation: Department of Internal Medicine and Medical SpecialtiesUniversity 'Sapienza', Rome, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Filetti
authors.affiliation: Department of Internal Medicine and Medical SpecialtiesUniversity 'Sapienza', Rome, Italy.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Durante
authors.affiliation: Department of Health SciencesUniversity of Catanzaro 'Magna Graecia', Catanzaro, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Russo
authors.affiliation: Department of Developmental and Molecular BiologyAlbert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Arturo
authors.initials: A
authors.lastname: Orlacchio
authors.affiliation: Department of Developmental and Molecular BiologyAlbert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Cristofano
authors.affiliation: Department of Medical and Biological SciencesUniversity of Udine, Udine, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Di Loreto
authors.affiliation: Department of Medical and Biological SciencesUniversity of Udine, Udine, Italy giuseppe.damante@uniud.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Damante
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002277:Carcinoma / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D013961:Thyroid Gland / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C561695:(+)-JQ1 compound; D000970:Antineoplastic Agents; D001381:Azepines; D018797:Cell Cycle Proteins; C489423:MCM5 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D014230:Triazoles; D001569:Benzodiazepines; C554645:molibresib
keywords: BET; MCM5; RNA-seq; epigenetics