Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition
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...
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2017-06-01
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| Series: | Tumor Biology |
| Online Access: | https://doi.org/10.1177/1010428317705034 |
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| author | Ming Ye Zejun Fang Hongqian Gu Rui Song Jiangwei Ye Hongzhang Li Zhiguang Wu Shenghui Zhou Peng Li Xiang Cai Xiaokun Ding Songshan Yu |
| author_facet | Ming Ye Zejun Fang Hongqian Gu Rui Song Jiangwei Ye Hongzhang Li Zhiguang Wu Shenghui Zhou Peng Li Xiang Cai Xiaokun Ding Songshan Yu |
| author_sort | Ming Ye |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-29baf1fd1eb546aaa2828c1990de6213 |
| institution | OA Journals |
| issn | 1423-0380 |
| language | English |
| publishDate | 2017-06-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Tumor Biology |
| spelling | doaj-art-29baf1fd1eb546aaa2828c1990de62132025-08-20T02:37:36ZengSAGE PublishingTumor Biology1423-03802017-06-013910.1177/1010428317705034Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia conditionMing Ye0Zejun Fang1Hongqian Gu2Rui Song3Jiangwei Ye4Hongzhang Li5Zhiguang Wu6Shenghui Zhou7Peng Li8Xiang Cai9Xiaokun Ding10Songshan Yu11Department of General Surgery, Sanmen People’s Hospital of Zhejiang, Sanmen, ChinaCentral Laboratory, Sanmen People’s Hospital of Zhejiang, Sanmen, ChinaDepartment of General Surgery, Sanmen People’s Hospital of Zhejiang, Sanmen, ChinaDepartment of Pathology, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of General Surgery, Sanmen People’s Hospital of Zhejiang, Sanmen, ChinaDepartment of Gastroenterology, Sanmen People’s Hospital of Zhejiang, Sanmen, ChinaDepartment of General Surgery, Sanmen People’s Hospital of Zhejiang, Sanmen, ChinaDepartment of General Surgery, Sanmen People’s Hospital of Zhejiang, Sanmen, ChinaDepartment of General Surgery, Sanmen People’s Hospital of Zhejiang, Sanmen, ChinaDepartment of General Surgery, Sanmen People’s Hospital of Zhejiang, Sanmen, ChinaDepartment of General Surgery, Sanmen People’s Hospital of Zhejiang, Sanmen, ChinaCentral Laboratory, Sanmen People’s Hospital of Zhejiang, Sanmen, ChinaHypoxia 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.https://doi.org/10.1177/1010428317705034 |
| spellingShingle | Ming Ye Zejun Fang Hongqian Gu Rui Song Jiangwei Ye Hongzhang Li Zhiguang Wu Shenghui Zhou Peng Li Xiang Cai Xiaokun Ding Songshan Yu Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition Tumor Biology |
| title | Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition |
| title_full | Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition |
| title_fullStr | Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition |
| title_full_unstemmed | Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition |
| title_short | Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition |
| title_sort | histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia inducible factor 1α under hypoxia condition |
| url | https://doi.org/10.1177/1010428317705034 |
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