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.

Journal article

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.

Authors: Schietke, R; Warnecke, C; Wacker, I; Schödel, J; Mole, D

• Publication status: Published
• Journal: Journal of biological chemistry
• Volume: 285
• Issue: 9
• Pages: 6658-6669
• Publication date: 2010-02-01
• DOI: 10.1074/jbc.m109.042424
• EISSN: 1083-351X
• ISSN: 0021-9258
• Language: English
• Keywords: Up-Regulation; Cadherins; Cell Transformation, Neoplastic; Neoplasm Metastasis; Hypoxia-Inducible Factor 1, alpha Subunit; Cell Line; Gene Expression Regulation, Enzymologic; Protein-Lysine 6-Oxidase; RNA, Messenger; Amino Acid Oxidoreductases; Anoxia; Humans; Epithelial Cells; Mesoderm