The Histone Deacetylase Inhibitor, Vorinostat, Represses Hypoxia Inducible Factor 1 Alpha Expression through Translational Inhibition

Abstract

Hypoxia inducible factor 1α (HIF-1α) is a master regulator of tumor angiogenesis being one of the major targets for cancer therapy. Previous studies have shown that Histone Deacetylase Inhibitors (HDACi) block tumor angiogenesis through the inhibition of HIF-1α expression. As such, Vorinostat (Suberoylanilide Hydroxamic Acid/SAHA) and Romidepsin, two HDACis, were recently approved by the Food and Drug Administration (FDA) for the treatment of cutaneous T cell lymphoma. Although HDACis have been shown to affect HIF-1α expression by modulating its interactions with the Hsp70/Hsp90 chaperone axis or its acetylation status, the molecular mechanisms by which HDACis inhibit HIF-1α expression need to be further characterized. Here, we report that the FDA-approved HDACi Vorinostat/SAHA inhibits HIF-1α expression in liver cancer-derived cell lines, by a new mechanism independent of p53, prolyl-hydroxylases, autophagy and proteasome degradation. We found that SAHA or silencing of HDAC9 mechanism of action is due to inhibition of HIF-1α translation, which in turn, is mediated by the eukaryotic translation initiation factor - eIF3G. We also highlighted that HIF-1α translation is dramatically inhibited when SAHA is combined with eIF3H silencing. Taken together, we show that HDAC activity regulates HIF-1α translation, with HDACis such as SAHA representing a potential novel approach for the treatment of hepatocellular carcinoma.

HDAC6 regulates sensitivity to cell death in response to stress and post-stress recovery

“…Thus, our results demonstrate that HDAC6 depletion acetylates HIF-1α and promotes HIF-1α degradation under hypoxia. In agreement with this finding, the HDAC6-selective inhibitor Tubastatin A (Schoepflin et al 2016) and pan-HDACi SAHA (Hutt et al 2014) blocked HIF-1α activity via a direct effect on HIF-1α stability via its acetylation and degradation. These data suggest that HDAC6 directly binds to and deacetylates HIF-1α.…”

“…Stable HIF-1α translocates to the nucleus, dimerizes with HIF-1β, and activates the transcription of target genes that contain a hypoxia response element (HRE). Several studies using cancer cell lines have described a role for HDACs in regulating the stability and activity of HIF-1α Geng et al 2011;Hutt et al 2014;Kong et al 2006;Qian et al 2006), although the mechanisms of action vary widely according to cell type. For example, class II HDAC6 and HDAC4 are associated with HIF-1α, and inhibition of both HDACs reduces HIF-1α protein levels (Geng et al 2011;Kong et al 2006;Qian et al 2006).…”

Novel chemoimmunotherapeutic strategy for hepatocellular carcinoma based on a genome-wide association study

“…Promotion of the glycolytic pathway is known as the Warburg effect, providing efficient cellular energy production in cancers including HCC35. Therefore, this phenomenon of glycolysis reduction was presumably associated with the induction of the expression of tumor suppressor genes that reduce glycolysis (Supplementary Figure S5A), and inhibition of metabolic oncogenes, as exemplified by hypoxia inducible factor1α in Huh7 cells36. Moreover, the glycolysis was possibly halted at late stages, as deduced from the accumulated Ala and lactic acid from pyruvic acid.…”

The epigenetic regulation of HIF-1α by SIRT1 in MPP + treated SH-SY5Y cells

“…Its downstream target genes, pathways and proteins can regulate the cell response due to a hypoxia-like stimulation [20]. HIF-1 is composed of the HIF-1α and HIF-1 β subunits; the latter is constitutively expressed in the nucleus, whereas HIF-1α is regulated by the environment [21–23]. Besides hypoxia, HIF-1α can be activated by environmental stimuli under normoxic conditions [23,24].…”

“…HIF-1 is composed of the HIF-1α and HIF-1 β subunits; the latter is constitutively expressed in the nucleus, whereas HIF-1α is regulated by the environment [21–23]. Besides hypoxia, HIF-1α can be activated by environmental stimuli under normoxic conditions [23,24]. Previous studies have found that the stability and function of HIF-1 is primarily regulated by posttranslational modifications [24].…”