Ye Ming, Fang Zejun, Gu Hongqian, Song Rui, Ye Jiangwei, Li Hongzhang, Wu Zhiguang, Zhou Shenghui, Li Peng, Cai Xiang, Ding Xiaokun, Yu Songshan
1 Department of General Surgery, Sanmen People's Hospital of Zhejiang, Sanmen, China.
2 Central Laboratory, Sanmen People's Hospital of Zhejiang, Sanmen, China.
Tumour Biol. 2017 Jun;39(6):1010428317705034. doi: 10.1177/1010428317705034.
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.
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。本研究旨在确定肝细胞癌中缺氧诱导因子-1α失调的新机制。我们发现，组蛋白去乙酰化酶5是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增强了肝癌细胞的迁移和侵袭能力。此外，组蛋白去乙酰化酶5通过沉默同源结构域相互作用蛋白激酶-2的表达诱导缺氧诱导因子-1α的转录，这也依赖于缺氧。然后敲低缺氧诱导因子-1α降低了间充质标志物N-钙黏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-钙黏蛋白增加。表型实验表明，敲低组蛋白去乙酰化酶5或缺氧诱导因子-1α会损害肝癌细胞的迁移和侵袭能力，但在肝癌细胞中消除同源结构域相互作用蛋白激酶-2时则会恢复，这表明组蛋白去乙酰化酶5-同源结构域相互作用蛋白激酶-2-缺氧诱导因子-1α通路在缺氧诱导的转移中起关键作用。最后，临床分析证实了肝细胞癌标本中组蛋白去乙酰化酶5与缺氧诱导因子-1α之间的正相关，以及组蛋白去乙酰化酶5和缺氧诱导因子-1α水平高的患者预后相对较差。综上所述，我们的研究结果揭示了肝细胞癌中组蛋白去乙酰化酶5与缺氧诱导因子-1之间相互作用的新机制。
