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 r...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2010
|
| _version_ | 1826289367470047232 |
|---|---|
| author | Schietke, R Warnecke, C Wacker, I Schödel, J Mole, D Campean, V Amann, K Goppelt-Struebe, M Behrens, J Eckardt, K Wiesener, MS |
| author_facet | Schietke, R Warnecke, C Wacker, I Schödel, J Mole, D Campean, V Amann, K Goppelt-Struebe, M Behrens, J Eckardt, K Wiesener, MS |
| author_sort | Schietke, R |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T02:27:48Z |
| format | Journal article |
| id | oxford-uuid:a6385f28-e807-434c-a6cd-f33a3090b4ac |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:27:48Z |
| publishDate | 2010 |
| record_format | dspace |
| spelling | oxford-uuid:a6385f28-e807-434c-a6cd-f33a3090b4ac2022-03-27T02:45:43ZThe 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 articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a6385f28-e807-434c-a6cd-f33a3090b4acEnglishSymplectic Elements at Oxford2010Schietke, RWarnecke, CWacker, ISchödel, JMole, DCampean, VAmann, KGoppelt-Struebe, MBehrens, JEckardt, KWiesener, MSHypoxia 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. |
| spellingShingle | Schietke, R Warnecke, C Wacker, I Schödel, J Mole, D Campean, V Amann, K Goppelt-Struebe, M Behrens, J Eckardt, K Wiesener, MS 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. |
| title | 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. |
| title_full | 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. |
| title_fullStr | 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. |
| title_full_unstemmed | 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. |
| title_short | 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. |
| title_sort | lysyl oxidases lox and loxl2 are necessary and sufficient to repress e cadherin in hypoxia insights into cellular transformation processes mediated by hif 1 |
| work_keys_str_mv | AT schietker thelysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT warneckec thelysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT wackeri thelysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT schodelj thelysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT moled thelysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT campeanv thelysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT amannk thelysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT goppeltstruebem thelysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT behrensj thelysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT eckardtk thelysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT wiesenerms thelysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT schietker lysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT warneckec lysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT wackeri lysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT schodelj lysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT moled lysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT campeanv lysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT amannk lysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT goppeltstruebem lysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT behrensj lysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT eckardtk lysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 AT wiesenerms lysyloxidasesloxandloxl2arenecessaryandsufficienttorepressecadherininhypoxiainsightsintocellulartransformationprocessesmediatedbyhif1 |