Inhibiting interactions of lysine demethylase LSD1 with snail/slug blocks cancer cell invasion.
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.
Department of Clinical and Diagnostic Medicine, University of Modena and R. Emilia, Modena, Italy.
Giovanna
G
Ferrari-Amorotti
Valentina
V
Fragliasso
Roza
R
Esteki
Zelia
Z
Prudente
Angela Rachele
AR
Soliera
Sara
S
Cattelani
Gloria
G
Manzotti
Giulia
G
Grisendi
Massimo
M
Dominici
Marco
M
Pieraccioli
Giuseppe
G
Raschellà
Claudia
C
Chiodoni
Mario Paolo
MP
Colombo
Bruno
B
Calabretta
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D020014:K562 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D014191:Tranylcypromine / Q000494:pharmacology
D015820:Cadherins; D004791:Enzyme Inhibitors; C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; C000604429:Snai1 protein, mouse; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014191:Tranylcypromine; D056466:Histone Demethylases; C495195:KDM1A protein, human