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.

译文

缺氧通过激活关键转录因子缺氧诱导因子-1在肝细胞癌的进展和转移中起关键作用。这项研究旨在确定低氧诱导因子-1α 在肝细胞癌中失调的新机制。我们发现,组蛋白去乙酰化酶5 (一种在肝细胞癌中高表达的组蛋白去乙酰化酶) 在缺氧而非常氧条件下加强了肝细胞癌细胞的迁移和侵袭。此外,组蛋白脱乙酰基酶5通过沉默同源结构域相互作用的蛋白激酶2表达来诱导缺氧诱导因子1α 的转录,这也依赖于缺氧。然后,低氧诱导因子-1α 的敲除降低了间充质标志物N-钙粘蛋白和波形蛋白以及基质金属蛋白酶MMP7和MMP9的表达; 然而,上皮标志物E-钙粘蛋白增加。表型实验表明,组蛋白去乙酰化酶5或缺氧诱导因子-1α 的敲除损害了肝癌细胞的迁移和侵袭,但在消除肝癌细胞中的同源结构域相互作用蛋白激酶-2时得以挽救,这表明组蛋白去乙酰化酶5-同源多蛋白相互作用蛋白kinase-2-hypoxia-inducible因子-1α 途径在缺氧诱导的转移中起关键作用。最后,临床分析证实了组蛋白去乙酰化酶5与低氧诱导因子-1α 在肝细胞癌标本中的正相关,并且对于高水平组蛋白去乙酰化酶5和低氧诱导因子-1α 的患者预后相对较差。总之,我们的发现证明了肝细胞癌中组蛋白去乙酰化酶5和缺氧诱导因子1之间串扰的新机制。

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