4-Hydroxynonenal Promotes Growth and Angiogenesis of Breast Cancer Cells through HIF-1α Stabilization

4-Hydroxynonenal (4-HNE) is a stable end product of lipid peroxidation, which has been shown to play animportant role in cell signal transduction, while increasing cell growth and differentiation. 4-HNE could inhibitphosphatase and tensin homolog (PTEN) activity in hepatocytes and increased levels have been found in humaninvasive breast cancer. Here we report that 4-HNE increased the cell growth of breast cancer cells as revealedby colony formation assay. Moreover, vascular endothelial growth factor (VEGF) expression was elevated,while protein levels of hypoxia inducible factor 1 alpha (HIF-1α) were up-regulated. Sirtuin-3 (SIRT3), a majormitochondria NAD+-dependent deacetylase, is reported to destabilize HIF-1α. Here, 4-HNE could inhibit thedeacetylase activity of SIRT3 by thiol-specific modification. We further demonstrated that the regulation by4-HNE of levels of HIF-1α and VEGF depends on SIRT3. Consistent with this, 4-HNE could not increase thecell growth in SIRT3 knockdown breast cancer cells. Additionally, 4-HNE promoted angiogenesis and invasionof breast cancer cells in a SIRT3-dependent manner. In conclusion, we propose that 4-HNE promotes growth,invasion and angiogenesis of breast cancer cells through the SIRT3-HIF-1α-VEGF axis.