No abstract

Histone deacetylase inhibitors (HDACIs) are currently in clinical trials partly due to their potent antiangiogenic effects. However, the detailed mechanism of their action is unclear. Here, we observed that several HDACIs (TSA, SB, Apicidin, and VPA) dramatically decreased HIF-1• protein level and transcriptional activity of HIF-1 in human and mouse tumor cell lines. Furthermore, class I HDACs, HDAC1 and 3 enhanced HIF-1• stability and HIF-1 transactivation function in hypoxic conditions. In addition, immunoprecipitation and in vitro binding assays revealed that HDAC1 and 3 directly bind to the oxygen-dependent degradation domain of HIF-1•. Collectively, these results suggest that HDAC1 and 3 are considered as a positive regulator of HIF-1• stability via direct interaction and may play an important role in HIF-1-induced tumor angiogenesis.

Abstract. Hypoxia-inducible factor-1 (HIF-1) has a central role in cellular responses to hypoxia, including the transcriptional activation of a number of genes involved in angiogenesis in tumors. We found that curcumin, a natural, biologically active compound isolated from the commonly used spice turmeric, significantly decreases hypoxia-induced HIF-1· protein levels in HepG2 hepatocellular carcinoma cells. Moreover, curcumin suppressed the transcriptional activity of HIF-1 under hypoxia, leading to a decrease in the expression of vascular endothelial growth factor (VEGF), a major HIF-1 target angiogenic factor. Curcumin also blocked hypoxia-stimulated angiogenesis in vitro and down-regulated HIF-1· and VEGF expression in vascular endothelial cells. These findings suggest that curcumin may play pivotal roles in tumor suppression via the inhibition of HIF-1·-mediated angiogenesis.

No abstract

Visfatin has been originally identified as a growth factor for early stage B cells and recently known as an adipokine. Here, we report that hypoxia induces the visfatin mRNA and protein levels in MCF7 breast cancer cells. We also demonstrate that induction of visfatin gene is regulated by hypoxia-inducible factor-1a (HIF-1a). Moreover, 50 -flanking promoter region of human visfatin gene contains two functional HIF responsive elements (HREs), activating the expression of visfatin. Mutation of these HREs in the visfatin promoter abrogates activation of a luciferase reporter gene driven by visfatin promoter under hypoxia. Taken together, our results demonstrate that visfatin is a new hypoxia-inducible gene of which expression is stimulated through the interaction of HIF-1 with HRE sites in its promoter region.