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

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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; Rotili, Dante; Liu, Ning Qing; Novakovic, Boris; 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.

In: Cancers, Vol. 11, No. 12, 2027, 2019.

Research output: Contribution to journalArticle

Harvard

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 2019, 'Inhibition of histone demethylases LSD1 and UTX regulates ERα signaling in breast cancer', Cancers, vol. 11, no. 12, 2027. https://doi.org/10.3390/cancers11122027

APA

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., ... Altucci, L. (2019). Inhibition of histone demethylases LSD1 and UTX regulates ERα signaling in breast cancer. Cancers, 11(12), [2027]. https://doi.org/10.3390/cancers11122027

CBE

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. 2019. Inhibition of histone demethylases LSD1 and UTX regulates ERα signaling in breast cancer. Cancers. 11(12):Article 2027. https://doi.org/10.3390/cancers11122027

MLA

Vancouver

Author

Benedetti, Rosaria ; Dell’aversana, Carmela ; De Marchi, Tommaso ; Rotili, Dante ; Liu, Ning Qing ; Novakovic, Boris ; 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. / Inhibition of histone demethylases LSD1 and UTX regulates ERα signaling in breast cancer. In: Cancers. 2019 ; Vol. 11, No. 12.

RIS

TY - JOUR

T1 - Inhibition of histone demethylases LSD1 and UTX regulates ERα signaling in breast cancer

AU - Benedetti, Rosaria

AU - Dell’aversana, Carmela

AU - De Marchi, Tommaso

AU - Rotili, Dante

AU - Liu, Ning Qing

AU - Novakovic, Boris

AU - Boccella, Serena

AU - Di Maro, Salvatore

AU - Cosconati, Sandro

AU - Baldi, Alfonso

AU - Niméus, Emma

AU - Schultz, Johan

AU - Höglund, Urban

AU - Maione, Sabatino

AU - Papulino, Chiara

AU - Chianese, Ugo

AU - Iovino, Francesco

AU - Federico, Antonio

AU - Mai, Antonello

AU - Stunnenberg, Hendrik G.

AU - Nebbioso, Angela

AU - Altucci, Lucia

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - ERα 4

KW - Hormone signaling 5

KW - KDM inhibitor 1

KW - LSD1 2

KW - UTX 3

U2 - 10.3390/cancers11122027

DO - 10.3390/cancers11122027

M3 - Article

C2 - 31888209

AN - SCOPUS:85077269849

VL - 11

JO - Cancers

JF - Cancers

SN - 2072-6694

IS - 12

M1 - 2027

ER -