Pigment epithelium-derived factor (PEDF), a member of the
serine protease inhibitor (
SERPIN) superfamily, displays a potent antiangiogenic and antimetastatic activity in a broad range of
tumor types. Melanocytes and low aggressive
melanoma cells secrete high levels of PEDF, while its expression is lost in highly aggressive
melanomas. PEDF efficiently abrogates a number of functional properties critical for the acquisition of metastatic ability by
melanoma cells, such as neovascularization, proliferation, migration, invasiveness and extravasation. In this study, we identify
hypoxia as a relevant negative regulator of PEDF in melanocytes and low aggressive
melanoma cells. PEDF was regulated at the
protein level. Importantly, although downregulation of PEDF was induced by inhibition of 2-oxoglutarate-dependent
dioxygenases, it was independent of the
hypoxia inducible factor (HIF), a key mediator of the adaptation to
hypoxia. Decreased PEDF
protein was not mediated by inhibition of translation through
untranslated regions (
UTRs) in
melanoma cells. Degradation by
metalloproteinases, implicated on PEDF degradation in
retinal pigment epithelial cells, or by the
proteasome, was also excluded as regulatory mechanism in
melanoma cells. Instead, we found that degradation by autophagy was critical for PEDF downregulation under
hypoxia in human
melanoma cells. Our findings show that hypoxic conditions encountered during primary
melanoma growth downregulate antiangiogenic and antimetastasic PEDF by a posttranslational mechanism involving degradation by autophagy and could therefore contribute to the acquisition of highly metastatic potential characteristic of aggressive
melanoma cells.