BET inhibitors induce NF-κB and E2F downregulation in Hodgkin and Reed-Sternberg cells.

Autor: Fernández S; Translational Research Laboratory, MD Anderson Cancer Center Madrid, Spain., Díaz E; Translational Research Laboratory, MD Anderson Cancer Center Madrid, Spain., Rita CG; Flow Cytometry Unit, Eurofins-Megalab, MD Anderson Cancer Center Madrid, Spain., Estévez M; Department of Hematology, MD Anderson Cancer Center Madrid, Spain., Montalbán C; Department of Hematology, MD Anderson Cancer Center Madrid, Spain., García JF; Translational Research Laboratory, MD Anderson Cancer Center Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain. Electronic address: jfgarcia@mdanderson.es.
Jazyk: angličtina
Zdroj: Experimental cell research [Exp Cell Res] 2023 Sep 15; Vol. 430 (2), pp. 113718. Date of Electronic Publication: 2023 Jul 17.
DOI: 10.1016/j.yexcr.2023.113718
Abstrakt: The prognosis of patients with relapsed and/or refractory classic Hodgkin lymphoma (cHL) continues to be poor. Therefore, there is a continuing need to develop novel therapies and to rationalize the use of target combinations. In recent years there has been growing interest in epigenetic targets for hematological malignancies under the rationale of the presence of common alterations in epigenetic transcriptional regulation. Since Hodgkin and Reed-Sternberg (HRS) cells have frequent inactivating mutations of the CREBBP and EP300 acetyltransferases, bromodomain and extra-terminal (BET) inhibitors can be a rational therapy for cHL. Here we aimed to confirm the efficacy of BET inhibitors (iBETs) using representative cell models and functional experiments, and to further explore biological mechanisms under iBET treatment using whole-transcriptome analyses. Our results reveal cytostatic rather than cytotoxic activity through the induction of G1/S and G2/M cell-cycle arrest, in addition to variable MYC downregulation. Additionally, massive changes in the transcriptome induced by the treatment include downregulation of relevant pathways in cHL disease: NF-kB and E2F, among others. Our findings support the therapeutic use of iBETs in selected cHL patients and reveal previously unknown biological mechanisms and consequences of pan-BET inhibition.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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