Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Small Molecule Inhibitors of KDM5 Histone Demethylases Increase Radio-Sensitivity of Breast Cancer Cells Over-Expressing JARID1B

Simone Pippa
,
Cecilia Mannironi
,
Valerio Licursi
,
Luca Bombardi
,
Gianni Colotti
,
Enrico Cundari
,
Adriano Mollica
,
Antonio Coluccia
ORCID logo ,
Valentina Naccarato
,
Giuseppe La Regina
,
Romano Silvestri
ORCID logo ,
Rodolfo Negri
*
Version 1 : Received: 7 June 2018 / Approved: 8 June 2018 / Online: 8 June 2018 (12:29:10 CEST)

How to cite: Pippa, S.; Mannironi, C.; Licursi, V.; Bombardi, L.; Colotti, G.; Cundari, E.; Mollica, A.; Coluccia, A.; Naccarato, V.; La Regina, G.; Silvestri, R.; Negri, R. Small Molecule Inhibitors of KDM5 Histone Demethylases Increase Radio-Sensitivity of Breast Cancer Cells Over-Expressing JARID1B. Preprints 2018, 2018060131. https://doi.org/10.20944/preprints201806.0131.v1 Pippa, S.; Mannironi, C.; Licursi, V.; Bombardi, L.; Colotti, G.; Cundari, E.; Mollica, A.; Coluccia, A.; Naccarato, V.; La Regina, G.; Silvestri, R.; Negri, R. Small Molecule Inhibitors of KDM5 Histone Demethylases Increase Radio-Sensitivity of Breast Cancer Cells Over-Expressing JARID1B. Preprints 2018, 2018060131. https://doi.org/10.20944/preprints201806.0131.v1

Abstract

Background: KDM5 enzymes are H3K4 specific histone demethylases involved in transcriptional regulation and DNA repair. These proteins are over-expressed in different kinds of cancer, including breast, prostate and bladder carcinoma, with positive effects on cancer proliferation and chemo-resistance. For these reasons, these enzymes are potential therapeutic cancer 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 JARID1B. In particular we tested H3K4 demethylation (western blot); target gene transcription (RNAseq and real time PCR); radio-sensitivity (citoxicity and clonogenic assays) and damage accumulation (kinetics of H2AX phosphorylation). Results: we show that two compounds with completely different chemical structure can selectively inhibit KDM5 enzymes and that both compounds are capable of increasing sensitivity of breast cancer cells to ionizing radiation and H2AX phosphorylation. Conclusions: These findings confirm the involvement of H3K4 specific demethylases in DNA damage signaling and repair and suggest new strategies for the therapeutic use of their inhibitors.

Keywords

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

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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