A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression.
The transcription factor Snail controls epithelial-mesenchymal transitions (EMT) by repressing E-cadherin expression and other epithelial genes. However, the mechanisms involved in the regulation of Snail function are not fully understood. Here we show that lysyl-oxidase-like 2 and 3 (LOXL2 and LOXL3), two members of the lysyl-oxidase gene family, interact and cooperate with Snail to downregulate E-cadherin expression. Snail's lysine residues 98 and 137 are essential for Snail stability, functional cooperation with LOXL2/3 and induction of EMT. Overexpression of LOXL2 or LOXL3 in epithelial cells induces an EMT process, supporting their implication in tumor progression. The biological importance of LOXL2 is further supported by RNA interference of LOXL2 in Snail-expressing metastatic carcinoma cells, which led to a strong decrease of tumor growth associated to increased apoptosis and reduced expression of mesenchymal and invasive/angiogenic markers. Taken together, these results establish a direct link between LOXL2 and Snail in carcinoma progression.
Peinado
Héctor
H
Departamento de Bioquímica, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier, Madrid, Spain.
Del Carmen Iglesias-de la Cruz
Maria
M
Olmeda
David
D
Csiszar
Katalin
K
Fong
Keith S K
KS
Vega
Sonia
S
Nieto
Maria Angela
MA
Cano
Amparo
A
Portillo
Francisco
F
D000594:Amino Acid Oxidoreductases / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D017931:DNA Primers; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D051379:Mice; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
D015820:Cadherins; D017931:DNA Primers; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human; C435668:LOXL3 protein, human