Kong Xianguo, Lin Zhao, Liang Dongming, Fath Donna, Sang Nianli, Caro Jaime
Cardeza Foundation Hematologic Research and Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Mol Cell Biol. 2006 Mar;26(6):2019-28. doi: 10.1128/MCB.26.6.2019-2028.2006.
Adaptation to hypoxic microenvironment is critical for tumor survival and metastatic spread. Hypoxia-inducible factor 1alpha (HIF-1alpha) plays a key role in this adaptation by stimulating the production of proangiogenic factors and inducing enzymes necessary for anaerobic metabolism. Histone deacetylase inhibitors (HDACIs) produce a marked inhibition of HIF-1alpha expression and are currently in clinical trials partly based on their potent antiangiogenic effects. Although it has been postulated that HDACIs affect HIF-1alpha expression by enhancing its interactions with VHL (von Hippel Lindau), thus promoting its ubiquitination and degradation, the actual mechanisms by which HDACIs decrease HIF-1alpha levels are not clear. Here, we present data indicating that HDACIs induce the proteasomal degradation of HIF-1alpha by a mechanism that is independent of VHL and p53 and does not require the ubiquitin system. This degradation pathway involves the enhanced interaction of HIF-1alpha with HSP70 and is secondary to a disruption of the HSP70/HSP90 axis function that appears mediated by the activity of HDAC-6.
适应缺氧微环境对于肿瘤的存活和转移扩散至关重要。缺氧诱导因子1α（HIF-1α）通过刺激促血管生成因子的产生和诱导无氧代谢所需的酶，在这种适应过程中发挥关键作用。组蛋白去乙酰化酶抑制剂（HDACIs）对HIF-1α的表达有显著抑制作用，目前正处于临床试验阶段，部分原因是其强大的抗血管生成作用。尽管有人推测HDACIs通过增强HIF-1α与VHL（冯·希佩尔-林道蛋白）的相互作用来影响HIF-1α的表达，从而促进其泛素化和降解，但HDACIs降低HIF-1α水平的实际机制尚不清楚。在此，我们提供的数据表明，HDACIs通过一种独立于VHL和p53且不需要泛素系统的机制诱导HIF-1α的蛋白酶体降解。这种降解途径涉及HIF-1α与HSP70相互作用的增强，并且是由HDAC-6的活性介导的HSP70/HSP90轴功能破坏的继发结果。
