Inhibiting interactions of lysine demethylase LSD1 with snail/slug blocks cancer cell invasion

Giovanna Ferrari-Amorotti, Valentina Fragliasso, Roza Esteki, Zelia Prudente, Angela Rachele Soliera, Sara Cattelani, Gloria Manzotti, Giulia Grisendi, Massimo Dominici, Marco Pieraccioli, Giuseppe Raschellà, Claudia Chiodoni, Mario Paolo Colombo, Bruno Calabretta

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

The process of epithelial-mesenchymal transition (EMT) which is required for cancer cell invasion is regulated by a family of E-box-binding transcription repressors, which include Snail (SNAIL1) and Slug (SNAI2). Snail appears to repress the expression of the EMT marker E-cadherin by epigenetic mechanisms dependent on the interaction of its N-terminal SNAG domain with chromatin-modifying proteins including lysine-specific demethylase 1 (LSD1/KDM1A). We assessed whether blocking Snail/Slug-LSD1 interaction by treatment with Parnate, an enzymatic inhibitor of LSD1, or TAT-SNAG, a cell-permeable peptide corresponding to the SNAG domain of Slug, suppresses the motility and invasiveness of cancer cells of different origin and genetic background. We show here that either treatment blocked Slug-dependent repression of the E-cadherin promoter and inhibited the motility and invasion of tumor cell lines without any effect on their proliferation. These effects correlated with induction of epithelial and repression of mesenchymal markers and were phenocopied by LSD1 or Slug downregulation. Parnate treatment also inhibited bone marrow homing/engraftment of Slug-expressing K562 cells. Together, these studies support the concept that targeting Snail/Slug-dependent transcription repression complexes may lead to the development of novel drugs selectively inhibiting the invasive potential of cancer cells.

Original languageEnglish
Pages (from-to)235-245
Number of pages11
JournalCancer Research
Volume73
Issue number1
DOIs
Publication statusPublished - Jan 1 2013

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Gastropoda
Snails
Lysine
Neoplasms
Tranylcypromine
Epithelial-Mesenchymal Transition
Cadherins
K562 Cells
Tumor Cell Line
Epigenomics
Chromatin
Down-Regulation
Bone Marrow
Peptides
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Ferrari-Amorotti, G., Fragliasso, V., Esteki, R., Prudente, Z., Soliera, A. R., Cattelani, S., ... Calabretta, B. (2013). Inhibiting interactions of lysine demethylase LSD1 with snail/slug blocks cancer cell invasion. Cancer Research, 73(1), 235-245. https://doi.org/10.1158/0008-5472.CAN-12-1739

Inhibiting interactions of lysine demethylase LSD1 with snail/slug blocks cancer cell invasion. / Ferrari-Amorotti, Giovanna; Fragliasso, Valentina; Esteki, Roza; Prudente, Zelia; Soliera, Angela Rachele; Cattelani, Sara; Manzotti, Gloria; Grisendi, Giulia; Dominici, Massimo; Pieraccioli, Marco; Raschellà, Giuseppe; Chiodoni, Claudia; Colombo, Mario Paolo; Calabretta, Bruno.

In: Cancer Research, Vol. 73, No. 1, 01.01.2013, p. 235-245.

Research output: Contribution to journalArticle

Ferrari-Amorotti, G, Fragliasso, V, Esteki, R, Prudente, Z, Soliera, AR, Cattelani, S, Manzotti, G, Grisendi, G, Dominici, M, Pieraccioli, M, Raschellà, G, Chiodoni, C, Colombo, MP & Calabretta, B 2013, 'Inhibiting interactions of lysine demethylase LSD1 with snail/slug blocks cancer cell invasion', Cancer Research, vol. 73, no. 1, pp. 235-245. https://doi.org/10.1158/0008-5472.CAN-12-1739
Ferrari-Amorotti G, Fragliasso V, Esteki R, Prudente Z, Soliera AR, Cattelani S et al. Inhibiting interactions of lysine demethylase LSD1 with snail/slug blocks cancer cell invasion. Cancer Research. 2013 Jan 1;73(1):235-245. https://doi.org/10.1158/0008-5472.CAN-12-1739
Ferrari-Amorotti, Giovanna ; Fragliasso, Valentina ; Esteki, Roza ; Prudente, Zelia ; Soliera, Angela Rachele ; Cattelani, Sara ; Manzotti, Gloria ; Grisendi, Giulia ; Dominici, Massimo ; Pieraccioli, Marco ; Raschellà, Giuseppe ; Chiodoni, Claudia ; Colombo, Mario Paolo ; Calabretta, Bruno. / Inhibiting interactions of lysine demethylase LSD1 with snail/slug blocks cancer cell invasion. In: Cancer Research. 2013 ; Vol. 73, No. 1. pp. 235-245.
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