Small Molecule Inhibitors of KDM5 Histone Demethylases Increase the Radiosensitivity of Breast Cancer Cells Overexpressing JARID1B

Molecules. 2019 May 4;24(9):1739. doi: 10.3390/molecules24091739.

Simone Pippa ¹, Cecilia Mannironi ², Valerio Licursi ³ ⁴, Luca Bombardi ⁵, Gianni Colotti ⁶, Enrico Cundari ⁷, Adriano Mollica ⁸, Antonio Coluccia ⁹, Valentina Naccarato ¹⁰, Giuseppe La Regina ¹¹, Romano Silvestri ¹², Rodolfo Negri ¹³ ¹⁴

Affiliations

1 Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, 00185 Rome, Italy. [email protected].
2 Institute of Molecular Biology and Pathology, Italian National Research Council, 00185 Rome, Italy. [email protected].
3 Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, 00185 Rome, Italy. [email protected].
4 Institute for Systems Analysis and Computer Science "A. Ruberti", Italian National Research Council, 00185 Rome, Italy. [email protected].
5 Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, 00185 Rome, Italy. [email protected].
6 Institute of Molecular Biology and Pathology, Italian National Research Council, 00185 Rome, Italy. [email protected].
7 Institute of Molecular Biology and Pathology, Italian National Research Council, 00185 Rome, Italy. [email protected].
8 Department of Pharmacy, University "G. d' Annunzio" of Chieti, Via dei Vestini 31, 66100 Chieti, Italy. [email protected].
9 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia Cenci Bolognetti Foundation, Sapienza University of Rome, 00185 Rome, Italy. [email protected].
10 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia Cenci Bolognetti Foundation, Sapienza University of Rome, 00185 Rome, Italy. [email protected].
11 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia Cenci Bolognetti Foundation, Sapienza University of Rome, 00185 Rome, Italy. [email protected].
12 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia Cenci Bolognetti Foundation, Sapienza University of Rome, 00185 Rome, Italy. [email protected].
13 Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, 00185 Rome, Italy. [email protected].
14 Institute of Molecular Biology and Pathology, Italian National Research Council, 00185 Rome, Italy. [email protected].

PMID: 31060229 DOI: 10.3390/molecules24091739

Abstract

Background: KDM5 Enzymes are H3K4 specific histone demethylases involved in transcriptional regulation and DNA repair. These proteins are overexpressed in different kinds of Cancer, including breast, prostate and bladder carcinomas, with positive effects on Cancer proliferation and chemoresistance. For these reasons, these Enzymes are potential therapeutic targets. Methods: In the present study, we analyzed the effects of three different inhibitors of KDM5 Enzymes in MCF-7 breast Cancer cells over-expressing one of them, namely KDM5B/JARID1B. In particular we tested H3K4 demethylation (western blot); radio-sensitivity (cytoxicity and clonogenic assays) and damage accumulation (COMET assay and kinetics of H2AX phosphorylation). Results: we show that all three compounds with completely different chemical structures can selectively inhibit KDM5 Enzymes and are capable of increasing sensitivity of breast Cancer cells to ionizing radiation and radiation-induced damage. Conclusions: These findings confirm the involvement of H3K4 specific demethylases in the response to DNA damage, show a requirement of the catalytic function and suggest new strategies for the therapeutic use of their inhibitors.

Keywords

DNA damage; breast cancer; epigenetic drugs; histone demethylase inhibitors.

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