The Lysyl Oxidases LOX and LOXL2 Are Necessary and Sufficient to Repress E-cadherin in Hypoxia

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.Constant availability of molecular oxygen is crucial for the structure and function of any mammalian cell. Therefore, cellular responses to reduced oxygen tensions (hypoxia) play an important role in development and many aspects of physiological homeostasis. Many important disease processes, including ischemic vascular diseases and cancer, involve reduced tissue oxygenation, and cellular adaptation to this is implicated in disease progression and clinical outcome. The hypoxia-inducible transcription factor (HIF) 2 is a central mechanism responding to low cellular oxygenation and mediates a variety of systemic and local adaptive responses, including the control of red cell production, regulation of angiogenesis, modulation of vascular tone, enhancement of glycolysis, and cellular glucose uptake (for a review, see Refs. 1-3). HIF consists of a heterodimer of ␣-and ␤-subunits, both being basic helix-loop-helix-Per Arnt Sim domain proteins. Whereas HIF␤ is constitutively expressed, HIF␣ subunits are unstable and inversely correlated to the availability of molecular oxygen. At least two oxygen-regulated isoforms of HIF␣ have been identified, HIF-1␣ and HIF-2␣, sharing a high degree of sequence homology and a similar domain structure (4). Regulation of HIF is primarily governed by oxygen-dependent hydroxylation of its HIF␣ subunits, which influences protein stability and transcriptional activity.Growth and behavior of tumor cells is strongly dependent on their microenvironment, where hypoxia is both a stress factor and an important signal (for a review, see Refs. 5 and 6). Dating back to 1927, Otto Warburg had already described that tumor cells have a much increased utilization of the glycolytic pathway (7). Since then, a number of studies have established that indeed HIF is necessary to activate glycolysis in tumor cells in order to maintain energy homeosta...

Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis

“…Our studies demonstrate that miR-199a suppresses LOX expression in ovarian cancer cells. LOX is induced by HIF-1, cross-links collagens, and facilitates tumor metastasis (7,22,23). Hypoxia affects modification of collagens and metastasis of sarcomas (24).…”

“…LOX cross-links collagens and is induced by HIF-1α. Moreover, LOX affects tumor cell migration and metastasis (7,11). miR-199a transfection abrogated LOX expression under hypoxia (Fig.…”

“…HIF-1α/HIF-2α are stabilized in hypoxia and associate with hypoxia-inducible factor-1β (HIF-1β) to form heterodimeric transcription factors and induce the expression of target genes (5,6). HIF-1-mediated expression of lysyloxidase (LOX) cross-links collagens and induces cell migration (7). Epithelial ovarian cancer cells (EOCCs) that have adapted to hypoxia by activating HIF-1 disseminate from primary ovarian tumors and exfoliate into the peritoneal cavity.…”

Expression and Significance of Hypoxia Inducible Factor-1α and Lysyl Oxidase in Non-small Cell Lung Cancer

“…Erler et al indentified LOX as a target of HIF-1α and showed LOX-mediated hypoxia induced invasion through cell-ECM adhesion and activation (Erler et al, 2006). LOX has been shown to mediate an induction of Epithelialmesenchymal transition, owing to LOX being the target of HIF-1α (Schietke et al, 2010). Moreover, in addition to establishing HIF-1α-dependent LOX action on tumor, LOX could upregulate HIF-1α protein expression in a manner requiring LOX-mediated hydrogen peroxide production in colorectal adenocarcinoma cells (Pez et al, 2011).…”

Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis

“…Finally, EMT inductors, such as hypoxia and TGFβ, promote Loxl2 gene expression [176,177], and the LOXL2 protein, in turn, interacts and stabilizes the SNAIL1 transcription factor to repress epithelial-specific gene promoters [176,177].…”