Article
- The EMBO Journal (2005) 24, 3446 - 3458
- doi:10.1038/sj.emboj.7600781
Published online: 18 August 2005
Subject Categories:
A molecular role for lysyl oxidase-like 2 enzyme in Snail regulation and tumor progression
Héctor Peinado1,a, Maria del Carmen Iglesias-de la Cruz1,a, David Olmeda1, Katalin Csiszar2, Keith SK Fong2, Sonia Vega3,b, Maria Angela Nieto3,b, Amparo Cano1 and Francisco Portillo1
- Departamento de Bioquímica, Instituto de Investigaciones Biomédicas 'Alberto Sols', Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier, Madrid, Spain
- Cardiovascular Research Center, John A Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
- Instituto Cajal, Avenida Doctor Arce, Madrid, Spain
Correspondence to:
Amparo Cano, Instituto de Investigaciones Biomédicas 'Alberto Sols', CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain. Tel.: +34 91 585 4411; Fax: +34 91 585 4401; E-mail: acano@iib.uam.es
Francisco Portillo, Instituto de Investigaciones Biomédicas 'Alberto Sols', CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain. Tel.: +34 91 585 4457; Fax: +34 91 585 4401; E-mail: fportillo@iib.uam.es
aThese authors contributed equally to this work
bPresent address: Instituto de Neurociencias, Apartado de Correos, 18, 03550 San Juan, Alicante, Spain
Received 1 March 2005; Accepted 20 July 2005
Abstract
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.
Keywords:
- E-cadherin,
- EMT,
- LOXL,
- Snail,
- tumor progression
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