The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in hypoxia: insights into cellular transformation processes mediated by HIF-1.
Hypoxia has been shown to promote tumor metastasis and lead to therapy resistance. Recent work has demonstrated that hypoxia represses E-cadherin expression, a hallmark of epithelial to mesenchymal transition, which is believed to amplify tumor aggressiveness. The molecular mechanism of E-cadherin repression is unknown, yet lysyl oxidases have been implicated to be involved. Gene expression of lysyl oxidase (LOX) and the related LOX-like 2 (LOXL2) is strongly induced by hypoxia. In addition to the previously demonstrated LOX, we characterize LOXL2 as a direct transcriptional target of HIF-1. We demonstrate that activation of lysyl oxidases is required and sufficient for hypoxic repression of E-cadherin, which mediates cellular transformation and takes effect in cellular invasion assays. Our data support a molecular pathway from hypoxia to cellular transformation. It includes up-regulation of HIF and subsequent transcriptional induction of LOX and LOXL2, which repress E-cadherin and induce epithelial to mesenchymal transition. Lysyl oxidases could be an attractive molecular target for cancers of epithelial origin, in particular because they are partly extracellular.
Schietke
Ruth
R
Interdisciplinary Centre for Clinical Research, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
Warnecke
Christina
C
Wacker
Ingrid
I
Schödel
Johannes
J
Mole
David R
DR
Campean
Valentina
V
Amann
Kerstin
K
Goppelt-Struebe
Margarete
M
Behrens
Jürgen
J
Eckardt
Kai-Uwe
KU
Wiesener
Michael S
MS
D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000502:physiology*; D015820:Cadherins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D000860:Hypoxia / Q000201:enzymology / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D008648:Mesoderm / Q000166:cytology; D009362:Neoplasm Metastasis; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D015854:Up-Regulation / Q000235:genetics
D015820:Cadherins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human; D008249:Protein-Lysine 6-Oxidase