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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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 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.

Detaljer

Författare
  • Rosaria Benedetti
  • Carmela Dell’aversana
  • Dante Rotili
  • Ning Qing Liu
  • Boris Novakovic
  • Serena Boccella
  • Salvatore Di Maro
  • Sandro Cosconati
  • Alfonso Baldi
  • Johan Schultz
  • Urban Höglund
  • Sabatino Maione
  • Chiara Papulino
  • Ugo Chianese
  • Francesco Iovino
  • Antonio Federico
  • Antonello Mai
  • Hendrik G. Stunnenberg
  • Angela Nebbioso
  • Lucia Altucci
Enheter & grupper
Externa organisationer
  • Second University of Napels
  • Sapienza University of Rome
  • Radboud University Nijmegen
  • University of Melbourne
  • Skåne University Hospital
  • University of Tampere
  • Kancera AB
  • Adlego Biomedical AB
  • Princess Maxima Center for Pediatric Oncology/Hematology
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi

Nyckelord

Originalspråkengelska
Artikelnummer2027
TidskriftCancers
Volym11
Utgåva nummer12
StatusPublished - 2019
PublikationskategoriForskning
Peer review utfördJa