Lysyl Oxidases LOX and LOXL2 Are Necessary and Sufficient to Repress E-cadherin in Hypoxia: INSIGHTS INTO CELLULAR TRANSFORMATION PROCESSES MEDIATED BY HIF-1

• Published in: The Journal of biological chemistry Vol. 285; no. 9; pp. 6658 - 6669
• Main Authors: Schietke, Ruth, Warnecke, Christina, Wacker, Ingrid, Schödel, Johannes, Mole, David R, Campean, Valentina, Amann, Kerstin, Goppelt-Struebe, Margarete, Behrens, Jürgen, Eckardt, Kai-Uwe, Wiesener, Michael S
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 26.02.2010
• Subjects: Amino Acid Oxidoreductases - genetics; Amino Acid Oxidoreductases - physiology; Cadherins - antagonists & inhibitors; Cell Biology; Cell Line; Cell Transformation, Neoplastic; Epithelial Cells; Gene Expression Regulation, Enzymologic; Humans; Hypoxia - enzymology; Hypoxia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; Mesoderm - cytology; Neoplasm Metastasis; Protein-Lysine 6-Oxidase - genetics; Protein-Lysine 6-Oxidase - physiology; RNA, Messenger - analysis; Up-Regulation - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.042424

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.