AMPK-HDAC5 pathway facilitates nuclear accumulation of HIF-1α and functional activation of HIF-1 by deacetylating Hsp70 in the cytosol

Hypoxia-inducible factor 1 (HIF-1) transcriptionally promotes production of adenosine triphosphate (ATP) whereas AMPK senses and regulates cellular energy homeostasis. A histone deacetylase (HDAC) activity has been proven to be critical for HIF-1 activation but the underlying mechanism and its role in energy homesostasis remain unclear. Here, we demonstrate that HIF-1 activation depends on a cytosolic, enzymatically active HDAC5. HDAC5 knockdown impairs hypoxia-induced HIF-1α accumulation and HIF-1 transactivation, whereas HDAC5 overexpression enhances HIF-1α stabilization and nuclear translocation. Mechanistically, we show that Hsp70 is a cytosolic substrate of HDAC5; and hyperacetylation renders Hsp70 higher affinity for HIF-1α binding, which correlates with accelerated degradation and attenuated nuclear accumulation of HIF-1α. Physiologically, AMPK-triggered cytosolic shuttling of HDAC5 is critical; inhibition of either AMPK or HDAC5 impairs HIF-1α nuclear accumulation under hypoxia or low glucose conditions. Finally, we show specifically suppressing HDAC5 is sufficient to inhibit tumor cell proliferation under hypoxic conditions. Our data delineate a novel link between AMPK, the energy sensor, and HIF-1, the major driver of ATP production, indicating that specifically inhibiting HDAC5 may selectively suppress the survival and proliferation of hypoxic tumor cells.

缺氧诱导因子1（Hypoxia-inducible factor 1, HIF-1）可通过转录调控促进三磷酸腺苷（adenosine triphosphate, ATP）的合成，而腺苷酸活化蛋白激酶（AMPK）能够感知并调控细胞能量稳态。已有研究表明，组蛋白去乙酰化酶（histone deacetylase, HDAC）的活性对HIF-1的激活至关重要，但其具体分子机制以及其在能量稳态中的作用仍未阐明。本研究证实，HIF-1的激活依赖于一种定位于胞质且具有酶活性的组蛋白去乙酰化酶5（HDAC5）。HDAC5敲低会削弱缺氧诱导的HIF-1α积累与HIF-1反式激活活性，而过表达HDAC5则可增强HIF-1α的稳定性及其核转位能力。机制研究显示，热休克蛋白70（Hsp70）是HDAC5的胞质底物；高乙酰化修饰可提高Hsp70与HIF-1α的结合亲和力，这与HIF-1α的降解加速以及核积累减弱密切相关。在生理层面，AMPK介导的HDAC5胞质穿梭过程发挥关键作用：抑制AMPK或HDAC5，均会损伤缺氧或低糖条件下HIF-1α的核积累。最后，本研究证实，特异性抑制HDAC5即可有效抑制缺氧环境中肿瘤细胞的增殖。本研究的数据揭示了能量感受器AMPK与ATP生成的核心调控因子HIF-1之间的全新关联，表明特异性靶向抑制HDAC5或可选择性抑制缺氧肿瘤细胞的存活与增殖。