Hypoxia Increases ATX Expression by Histone Crotonylation in a HIF-2α-Dependent Manner

Autotaxin (ATX), the key enzyme that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC), is involved in tumorigenesis through the ATX-LPA axis and is regarded as a valuable target in tumor therapy. Hypoxia is a major feature of solid tumors and contributes to tumor development with striking alterations in the gene expression profile. Here, we show that hypoxia induces ATX expression in a hypoxia-inducible factor (HIF) 2α-dependent fashion in human colon cancer SW480 cells. HIF-2α is directly bound to specific hypoxia response elements (HREs) in the ATX promoter. Under hypoxic conditions, knockout or inhibition of ATX suppressed the migration of SW480 cells, which could be rescued by the addition of LPA, suggesting that the induction of ATX during hypoxia promotes cancer cell migration through the ATX-LPA axis. Further studies showed that ATX expression was induced by HIF-2α through recruiting p300/CBP, which led to crotonylation but not acetylation of histone H3 in the ATX promoter region during hypoxia. Moreover, elevation of cellular histone crotonylation levels could induce ATX expression under normoxic conditions. In conclusion, our findings reveal that ATX is induced in SW480 cells during hypoxia by histone crotonylation in a HIF-2α-dependent manner, while as a novel mechanism of ATX expression regulation, the upregulation of ATX expression by histone crotonylation is not confined to hypoxia.