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Inhibition of Histone Demethylases LSD1 and UTX Regulates ERα Signaling in Breast Cancer

Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
Institute Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS)-National Research Council (CNR) Via Sergio Pansini, 5-80131 Napoli, Italy
Department of Oncology and Pathology, Lund University, SE-221 00 Lund, Sweden
Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy
Department of Molecular Biology, Radboud University, 6500 HB Nijmegen, The Netherlands
Murdoch Children’s Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, Parkville Victoria 3052, Australia
Department of Experimental Medicine, Section of Pharmacology “L. Donatelli”, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, University of Campania ’Luigi Vanvitelli’, 81100 Caserta, Italy
Department of Surgery, Skånes University Hospital, 222 29 Lund, Sweden
Kancera AB, Banvaktsvagen 22, SE-17148 Solna, Sweden
Adlego Biomedical AB, P.O. Box 42, SE-751 03 Uppsala, Sweden
Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio 7, 80138 Naples, Italy
Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland
Prinses Maxima Centrum, Heidelberglaan 25, 3584CS Utrecht, The Netherlands
Authors to whom correspondence should be addressed.
Cancers 2019, 11(12), 2027;
Received: 19 November 2019 / Revised: 9 December 2019 / Accepted: 11 December 2019 / Published: 16 December 2019
(This article belongs to the Special Issue Targeting Solid Tumors)
In breast cancer, Lysine-specific demethylase-1 (LSD1) and other lysine demethylases (KDMs), such as Lysine-specific demethylase 6A also known as Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), are co-expressed and co-localize with estrogen receptors (ERs), suggesting the potential use of hybrid (epi)molecules to target histone methylation and therefore regulate/redirect hormone receptor signaling. Here, we report on the biological activity of a dual-KDM inhibitor (MC3324), obtained by coupling the chemical properties of tranylcypromine, a known LSD1 inhibitor, with the 2OG competitive moiety developed for JmjC inhibition. MC3324 displays unique features not exhibited by the single moieties and well-characterized mono-pharmacological inhibitors. Inhibiting LSD1 and UTX, MC3324 induces significant growth arrest and apoptosis in hormone-responsive breast cancer model accompanied by a robust increase in H3K4me2 and H3K27me3. MC3324 down-regulates ERα in breast cancer at both transcriptional and non-transcriptional levels, mimicking the action of a selective endocrine receptor disruptor. MC3324 alters the histone methylation of ERα-regulated promoters, thereby affecting the transcription of genes involved in cell surveillance, hormone response, and death. MC3324 reduces cell proliferation in ex vivo breast cancers, as well as in breast models with acquired resistance to endocrine therapies. Similarly, MC3324 displays tumor-selective potential in vivo, in both xenograft mice and chicken embryo models, with no toxicity and good oral efficacy. This epigenetic multi-target approach is effective and may overcome potential mechanism(s) of resistance in breast cancer. View Full-Text
Keywords: KDM inhibitor 1; LSD1 2; UTX 3; ERα 4; hormone signaling 5 KDM inhibitor 1; LSD1 2; UTX 3; ERα 4; hormone signaling 5
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MDPI and ACS Style

Benedetti, R.; Dell’Aversana, C.; De Marchi, T.; Rotili, D.; Liu, N.Q.; Novakovic, B.; Boccella, S.; Di Maro, S.; Cosconati, S.; Baldi, A.; Niméus, E.; Schultz, J.; Höglund, U.; Maione, S.; Papulino, C.; Chianese, U.; Iovino, F.; Federico, A.; Mai, A.; Stunnenberg, H.G.; Nebbioso, A.; Altucci, L. Inhibition of Histone Demethylases LSD1 and UTX Regulates ERα Signaling in Breast Cancer. Cancers 2019, 11, 2027.

AMA Style

Benedetti R, Dell’Aversana C, De Marchi T, Rotili D, Liu NQ, Novakovic B, Boccella S, Di Maro S, Cosconati S, Baldi A, Niméus E, Schultz J, Höglund U, Maione S, Papulino C, Chianese U, Iovino F, Federico A, Mai A, Stunnenberg HG, Nebbioso A, Altucci L. Inhibition of Histone Demethylases LSD1 and UTX Regulates ERα Signaling in Breast Cancer. Cancers. 2019; 11(12):2027.

Chicago/Turabian Style

Benedetti, Rosaria, Carmela Dell’Aversana, Tommaso De Marchi, Dante Rotili, Ning Q. Liu, Boris Novakovic, Serena Boccella, Salvatore Di Maro, Sandro Cosconati, Alfonso Baldi, Emma Niméus, Johan Schultz, Urban Höglund, Sabatino Maione, Chiara Papulino, Ugo Chianese, Francesco Iovino, Antonio Federico, Antonello Mai, Hendrik G. Stunnenberg, Angela Nebbioso, and Lucia Altucci. 2019. "Inhibition of Histone Demethylases LSD1 and UTX Regulates ERα Signaling in Breast Cancer" Cancers 11, no. 12: 2027.

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