title: Poly(ADP-ribose)-dependent regulation of Snail1 protein stability.
abstract: Snail1 is a master regulator of the epithelial-mesenchymal transition (EMT) and has been implicated in key tumor biological processes such as invasion and metastasis. It has been previously shown that poly(ADP-ribose) polymerase-1 (PARP-1) knockdown, but not PARP inhibition, downregulates the expression of Snail1. In this study we have characterized a novel regulatory mechanism controlling Snail1 protein expression through poly(ADP-ribosyl)ation. The effect is not only limited to repression of Snail1 transcription but also to downregulated Snail1 protein stability. PARP-1 (but not PARP-2) poly(ADP) ribosylates Snail1, both in vivo and in vitro, and interacts with Snail1, an association that is sensitive to PARP inhibitors. PARP inhibition has also clear effects on EMT phenotype of different tumor cells, including Snail1 downregulation, E-cadherin upregulation, decreased cell elongation and invasiveness. Therefore, this study reveals a new regulatory mechanism of Snail1 activation through poly(ADP-ribosyl)ation with consequences in malignant transformation through EMT.
authors.affiliation: Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain.
authors.forename: M I
authors.initials: MI
authors.lastname: Rodríguez
authors.forename: A
authors.initials: A
authors.lastname: González-Flores
authors.forename: F
authors.initials: F
authors.lastname: Dantzer
authors.forename: J
authors.initials: J
authors.lastname: Collard
authors.forename: A G
authors.initials: AG
authors.lastname: de Herreros
authors.forename: F J
authors.initials: FJ
authors.lastname: Oliver
mesh_terms: D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005464:Fluorobenzenes / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology; D010616:Phenanthrenes / Q000494:pharmacology; D010793:Phthalazines / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D055550:Protein Stability; D012878:Skin Neoplasms / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D015820:Cadherins; D004791:Enzyme Inhibitors; D005464:Fluorobenzenes; C506932:KU0058948; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D011064:Poly Adenosine Diphosphate Ribose; C499320:PARP1 protein, human; C483041:PARP2 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases