Hypoxia plays a critical role in the progression and
metastasis of
hepatocellular carcinoma by activating the key
transcription factor,
hypoxia-inducible factor-1. This study aims to identify the novel mechanisms underlying the dysregulation of
hypoxia-inducible factor-1α in
hepatocellular carcinoma. We found that
histone deacetylase 5, a highly expressed
histone deacetylase in
hepatocellular carcinoma, strengthened the migration and invasion of
hepatocellular carcinoma cells under
hypoxia but not normoxia condition. Furthermore,
histone deacetylase 5 induced the transcription of
hypoxia-inducible factor-1α by silencing homeodomain-interacting
protein kinase-2 expression, which was also dependent on
hypoxia. And then knockdown of
hypoxia-inducible factor-1α decreased the expressions of mesenchymal markers,
N-cadherin, and
Vimentin, as well as
matrix metalloproteinases, MMP7 and MMP9; however, the epithelial marker,
E-cadherin, increased. Phenotype experiments showed that the migration and invasion of
hepatocellular carcinoma cells were impaired by knockdown of
histone deacetylase 5 or
hypoxia-inducible factor-1α but rescued when eliminating homeodomain-interacting
protein kinase-2 in
hepatocellular carcinoma cells, which suggested the critical role of
histone deacetylase 5-homeodomain-interacting
protein kinase-2-hypoxia-inducible factor-1α pathway in
hypoxia-induced
metastasis. Finally, clinical analysis confirmed the positive correlation between
histone deacetylase 5 and
hypoxia-inducible factor-1α in
hepatocellular carcinoma specimens and a relatively poor prognosis for the patients with high levels of
histone deacetylase 5 and
hypoxia-inducible factor-1α. Taken together, our findings demonstrated a novel mechanism underlying the crosstalk between
histone deacetylase 5 and
hypoxia-inducible factor-1 in
hepatocellular carcinoma.