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

Abstract

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-1a accumulation and HIF-1 transactivation, whereas HDAC5 overexpression enhances HIF-1a stabilization and nuclear translocation. Mechanistically, we show that Hsp70 is a cytosolic substrate of HDAC5; and hyperacetylation renders Hsp70 higher affinity for HIF-1a binding, which correlates with accelerated degradation and attenuated nuclear accumulation of HIF-1a. Physiologically, AMPK-triggered cytosolic shuttling of HDAC5 is critical; inhibition of either AMPK or HDAC5 impairs HIF-1a 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.

Exogenous pyruvate facilitates cancer cell adaptation to hypoxia by serving as an oxygen surrogate

“…The AMPK pathway inhibits energy-consuming processes such as fatty acid synthesis and protein synthesis, and upregulates energy generation pathways to increase ATP levels [51]. Activated AMPK also facilitates the activation of HIF-1 by nuclear exporting HDAC5, which promotes HIF-1α maturation and nuclear localization [52]. In addition to HIF-1 and AMPK signaling pathways, hypoxia-caused ATP shortage and ROS accumulation may trigger other cellular adaptive responses including the endoplasmic reticulum (ER) stress response.…”

HDACs and HDAC Inhibitors in Cancer Development and Therapy

“…HDAC1 and HDAC4 directly deacetylate HIF-1α and block degradation of the protein (Yoo et al 2006; Geng et al 2011). Instead of regulating HIF-1α acetylation, HDAC5 and HDAC6 facilitate HIF-1α maturation and stabilization by deacetylating its chaperones, HSP70 and HSP90 (Kong et al 2006; Chen et al 2015). Inhibition of HDAC5 and 6 results in hyperacetylation of these chaperones, accumulation of the immature HIF-1α complex, and degradation of HIF-1α by the 20S proteasome.…”

Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition

“…As described in previous studies, cytosolic deacetylase activity of HDAC5 was necessary for HIF1α stabilization and HDAC5 knockdown resulted in proteasome-dependent HIF1a degradation. 15 Taken together, our molecular and clinical evidences suggested a crosstalk between HDACs and hypoxia in promoting HCC metastasis ( Figure 7). In HCC, hypoxia environment enhances the repression of HIPK2 by HDAC5 and thus activates the transcription of HIF1α.…”

“…14 In addition, HDAC5 could also facilitate the hypoxia-induced stabilization and nuclear accumulation of HIF1α. 15 Here, we found a novel mechanism for transcriptional regulation of HIF1α in response to hypoxia. Briefly, HDAC5 induces the transcription of HIF1α by blocking homeodomain-interacting protein kinase-2 (HIPK2) expression in hypoxic HCC cells.…”