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Inhibition of histone demethylases LSD1 and UTX regulates ERα signaling in breast cancer

Benedetti, Rosaria ; Dell’aversana, Carmela ; De Marchi, Tommaso LU ; Rotili, Dante ; Liu, Ning Qing ; Novakovic, Boris ; Boccella, Serena ; Di Maro, Salvatore ; Cosconati, Sandro and Baldi, Alfonso , et al. (2019) In Cancers 11(12).
Abstract

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... (More)

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.

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published
subject
keywords
ERα 4, Hormone signaling 5, KDM inhibitor 1, LSD1 2, UTX 3
in
Cancers
volume
11
issue
12
article number
2027
publisher
Multidisciplinary Digital Publishing Institute (MDPI)
external identifiers
  • pmid:31888209
  • scopus:85077269849
ISSN
2072-6694
DOI
10.3390/cancers11122027
language
English
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yes
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3198febe-ca83-47ad-958e-3a00a12face9
date added to LUP
2020-01-10 14:16:50
date last changed
2020-01-16 04:09:14
@article{3198febe-ca83-47ad-958e-3a00a12face9,
  abstract     = {<p>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.</p>},
  author       = {Benedetti, Rosaria and Dell’aversana, Carmela and De Marchi, Tommaso and Rotili, Dante and Liu, Ning Qing and Novakovic, Boris and Boccella, Serena and Di Maro, Salvatore and Cosconati, Sandro and Baldi, Alfonso and Niméus, Emma and Schultz, Johan and Höglund, Urban and Maione, Sabatino and Papulino, Chiara and Chianese, Ugo and Iovino, Francesco and Federico, Antonio and Mai, Antonello and Stunnenberg, Hendrik G. and Nebbioso, Angela and Altucci, Lucia},
  issn         = {2072-6694},
  language     = {eng},
  number       = {12},
  publisher    = {Multidisciplinary Digital Publishing Institute (MDPI)},
  series       = {Cancers},
  title        = {Inhibition of histone demethylases LSD1 and UTX regulates ERα signaling in breast cancer},
  url          = {http://dx.doi.org/10.3390/cancers11122027},
  doi          = {10.3390/cancers11122027},
  volume       = {11},
  year         = {2019},
}