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Inhibition of histo...
Inhibition of histone demethylases LSD1 and UTX regulates ERα signaling in breast cancer
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- Benedetti, Rosaria (författare)
- University of Campania Luigi Vanvitelli
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- Dell’aversana, Carmela (författare)
- University of Campania Luigi Vanvitelli
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- De Marchi, Tommaso (författare)
- Lund University,Lunds universitet,Bröstcancer Proteogenomik,Forskargrupper vid Lunds universitet,Breast cancer Proteogenomics,Lund University Research Groups
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- Rotili, Dante (författare)
- Sapienza University of Rome
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- Liu, Ning Qing (författare)
- Radboud University Nijmegen
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- Novakovic, Boris (författare)
- University of Melbourne
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- Boccella, Serena (författare)
- University of Campania Luigi Vanvitelli
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- Di Maro, Salvatore (författare)
- University of Campania Luigi Vanvitelli
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- Cosconati, Sandro (författare)
- University of Campania Luigi Vanvitelli
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- Baldi, Alfonso (författare)
- University of Campania Luigi Vanvitelli
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- Niméus, Emma (författare)
- Lund University,Lunds universitet,Bröstcancer Proteogenomik,Forskargrupper vid Lunds universitet,Breast cancer Proteogenomics,Lund University Research Groups,Skåne University Hospital
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- Schultz, Johan (författare)
- Kancera AB
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- Höglund, Urban (författare)
- Adlego Biomedical AB
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- Maione, Sabatino (författare)
- University of Campania Luigi Vanvitelli
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- Papulino, Chiara (författare)
- University of Campania Luigi Vanvitelli
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- Chianese, Ugo (författare)
- University of Campania Luigi Vanvitelli
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- Iovino, Francesco (författare)
- University of Campania Luigi Vanvitelli
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- Federico, Antonio (författare)
- University of Tampere
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- Mai, Antonello (författare)
- Sapienza University of Rome
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- Stunnenberg, Hendrik G. (författare)
- Princess Maxima Center for Pediatric Oncology/Hematology,Radboud University Nijmegen
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- Nebbioso, Angela (författare)
- University of Campania Luigi Vanvitelli
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- Altucci, Lucia (författare)
- University of Campania Luigi Vanvitelli
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(creator_code:org_t)
- 2019-12-16
- 2019
- Engelska.
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 11:12
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://www.mdpi.com...
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https://lup.lub.lu.s...
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https://doi.org/10.3...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- ERα 4
- Hormone signaling 5
- KDM inhibitor 1
- LSD1 2
- UTX 3
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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Cancers
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- Av författaren/redakt...
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Benedetti, Rosar ...
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Dell’aversana, C ...
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De Marchi, Tomma ...
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Rotili, Dante
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Liu, Ning Qing
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Novakovic, Boris
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visa fler...
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Boccella, Serena
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Di Maro, Salvato ...
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Cosconati, Sandr ...
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Baldi, Alfonso
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Niméus, Emma
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Schultz, Johan
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Höglund, Urban
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Maione, Sabatino
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Papulino, Chiara
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Chianese, Ugo
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Iovino, Francesc ...
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Federico, Antoni ...
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Mai, Antonello
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Stunnenberg, Hen ...
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Nebbioso, Angela
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Altucci, Lucia
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Cancers
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