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

Ruth Schietke,Christina Warnecke,Ingrid Wacker,Johannes Schödel,David R Mole,Valentina Campean,Kerstin Amann,Margarete Goppelt-Struebe,Jürgen Behrens,Kai-Uwe Eckardt,Michael S Wiesener

doi:10.1074/jbc.m109.042424

Ruth Schietke, Christina Warnecke + Show 9 more

Open Access

https://doi.org/10.1074/jbc.m109.042424

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Abstract

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.

Highlights

Constant availability of molecular oxygen is crucial for the structure and function of any mammalian cell
hypoxia-inducible transcription factor (HIF)␣ is activated in the earliest renal lesions of the familial von Hippel Lindau (VHL) syndrome [18] and seems to be the decisive factor for growth initiation of experimental renal cell carcinoma (RCC), where HIF-2␣ plays the dominant role over HIF-1␣ (19 –23)
ZO-1 was strongly expressed in normoxic RCC10/VHL, where specific staining appeared as a continuous membranous pattern

Summary

Introduction

Constant availability of molecular oxygen is crucial for the structure and function of any mammalian cell. The HIF target gene lysyl oxidase (LOX) has been implicated in involvement in E-cadherin regulation. We demonstrate that LOXL2 is a direct HIF-1 target gene and that induction of lysyl oxidases is necessary and sufficient to repress E-cadherin in hypoxia.

Results

Conclusion