Inhibition of Histone Demethylases LSD1 and UTX Regulates ER alpha Signaling in Breast Cancer
| Autor: | Carmela Dell'Aversana, Antonello Mai, Dante Rotili, Boris Novakovic, Johan Schultz, Serena Boccella, Rosaria Benedetti, Ugo Chianese, Sabatino Maione, Francesco Iovino, Tommaso De Marchi, Urban Hoglund, Emma Niméus, Angela Nebbioso, Lucia Altucci, Hendrik G. Stunnenberg, Salvatore Di Maro, Alfonso Baldi, Sandro Cosconati, Chiara Papulino, Ning Qing Liu, Antonio Federico |
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| Přispěvatelé: | Benedetti, Rosaria, Dell'Aversana, Carmela, De Marchi, Tommaso, Rotili, Dante, Liu, Ning Qing, Novakovic, Bori, Boccella, Serena, Di Maro, Salvatore, Cosconati, Sandro, Baldi, Alfonso, Niméus, Emma, Schultz, Johan, Höglund, Urban, Maione, Sabatino, Papulino, Chiara, Chianese, Ugo, Iovino, Francesco, Federico, Antonio, Mai, Antonello, Stunnenberg, Hendrik G, Nebbioso, Angela, Altucci, Lucia |
| Rok vydání: | 2019 |
| Předmět: |
UTX 3
Cancer Research Estrogen receptor KDM inhibitor 1 Article ER? 4 LSD1 2 hormone signaling 5 03 medical and health sciences 0302 clinical medicine Breast cancer Histone methylation medicine Epigenetics Receptor Molecular Biology 030304 developmental biology 0303 health sciences ERα 4 biology medicine.disease 3. Good health Oncology Hormone receptor 030220 oncology & carcinogenesis biology.protein Cancer research Demethylase Histone Demethylases Hormone signaling 5 |
| Zdroj: | Cancers, 11 Cancers (Basel) 11 (2019). doi:10.3390/cancers11122027 info:cnr-pdr/source/autori:Benedetti R.; Dell'aversana C.; De Marchi T.; Rotili D.; Liu N.Q.; Novakovic B.; Boccella S.; Di Maro S.; Cosconati S.; Baldi A.; Nimeus E.; Schultz J.; Hoglund U.; Maione S.; Papulino C.; Chianese U.; Iovino F.; Federico A.; Mai A.; Stunnenberg H.G.; Nebbioso A.; Altucci L./titolo:Inhibition of histone demethylases LSD1 and UTX regulates ER? signaling in breast cancer/doi:10.3390%2Fcancers11122027/rivista:Cancers (Basel)/anno:2019/pagina_da:/pagina_a:/intervallo_pagine:/volume:11 Cancers, 11, 12 Cancers Volume 11 Issue 12 |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers11122027 |
| Popis: | 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 ER&alpha 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 ER&alpha 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. |
| Databáze: | OpenAIRE |
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